bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4623: Human anti-nucleolin antibodies with broad spectrum anticancer activity
Authors: Fernandes Daniel J. , Otake Yoko , Capizzi Robert L. 
Published: August 2012

Abstract
Extensive preclinical studies have validated nucleolin as a new therapeutic target in oncology. Confocal microscopy, immunohistochemistry, and cell fractionation studies have shown that this protein is highly overexpressed in the plasma membrane and cytoplasm of a wide variety of human hematological and solid tumor cells, but is usually undetectable on the cell surface or in the cytoplasm of the corresponding normal cells. We have utilized our licensed platform technology to generate a first-in-class panel of eight fully human monoclonal IgG1 antibodies (HuMAbs). These antibodies bind specifically to nucleolin on the tumor cell surface, which in turn elicits potent cytotoxicity to a variety of human tumor cell lines. One such example is CP101, which killed MV4-11 (AML), MCF-7 (breast), DU145 (prostate), PANC-1 and MIA PaCa-2 (pancreas) tumor cell lines with IC50 values ranging from (0.5-2.0 µg/ml; 3-12 nM) following exposure to the HuMAb for 96 hrs. These in vitro assays were performed in the absence of human complement and immune effector cells required for complement-dependent cellular cytotoxicity (CDCC) and antibody-dependent cellular cytotoxicity (ADCC), respectively. These results are consistent with published observations that anti-nucleolin HuMAbs can exploit the known shuttling function of cell surface nucleolin to gain intracellular access and induce direct tumor cytotoxicity. In contrast to its cytocidal effects on tumor cells, CP101 had no effect on the viability of either MCF-10A normal human breast epithelial cells or normal human CD19+ B cells, neither of which expresses nucleolin on the cell surface. In summary, the results suggest that anti-nucleolin HuMAbs are unique in that they can exert broad spectrum antitumor activity independently of the immune mechanism of CDCC and ADCC, while having no detectable effects on the viability of the corresponding normal 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 4623. doi:1538-7445.AM2012-4623
Abstract 4624: High affinity CD3 RECRUIT-TandAbs for T cell-mediated lysis of malignant CD19+ B cells
Authors: Reusch Uwe , Burkhardt Carmen , Knackmuss Stefan H. , Fucek Ivica , Eser Markus , McAleese Fionnuala , Gronewold Thomas , Zhukovsky Eugene , Little Melvyn 
Published: August 2012

Abstract
The TandAb technology enables the development of innovative antibody therapeutics for improved treatment of various diseases. This platform has been primarily applied to oncology and comprises of CD3 RECRUIT- and CD16A RECRUIT-TandAbs for activation of T and NK effector cells, respectively, and lysis of target cells expressing specific surface antigens. The CD3 RECRUIT-TandAb AFM11 is a human bispecific tetravalent antibody with two binding sites for the α-chain of CD3 and two binding sites for CD19. CD19 is expressed at early stages of B cell development and persists until the final differentiation into plasma cells. Thus, CD19 represents an attractive target for the treatment of various B cell malignancies including leukemias and lymphomas that lack CD20 expression or are refractory to anti-CD20 antibody therapies. In vitro cytotoxicity assays employing tumor cell lines demonstrate high potency of AFM11 in mediating target cell lysis: EC50 values are in the low to sub-picomolar range depending on CD19+ target cell lines and primary B-CLL tumor cells. Cytotoxic activity of tetravalent AFM11 is superior to those of alternative bivalent antibody formats. High affinity binding of AFM11 to CD3 and CD19 (low to sub-nanomolar range) contributes to efficacious T cell recruitment. This binding was determined by flow cytometry and by a label-free biosensor that measures real-time binding kinetics on live cells. Therapeutic recruitment of T cells has a potential for a devastating cytokine release if it results not in a site-specific but rather systemic activation. Thus, functional in vitro assays were used to demonstrate that high affinity and bivalent binding of AFM11 to CD3 is not sufficient for triggering activation signals in T cells. AFM11 activates T cells only in the presence of CD19+ target cells, and specifically mediates lysis of these cells without affecting antigen-negative bystander cells. In the absence of target cells and at high concentrations AFM11 induces down-modulation of the CD3/TCR complex from the surface of T cells. The latter may contribute additional safety to therapeutic potential of CD3 RECRUIT-TandAbs without affecting the efficacy, since AFM11-treated T cells can be re-engaged for target cell lysis. In vivo AFM11 demonstrated a robust dose-dependent inhibition of tumor growth in a study with Raji xenografts in NOD/scid mice and reconstituted human PBMC. Altogether, these data suggest that AFM11 is a highly efficacious novel drug candidate for the treatment of hematological malignancies and displays an advantageous safety profile.
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 4624. doi:1538-7445.AM2012-4624
Abstract 4627: Generation and characterization of non-competitive furin-inhibiting nanobodies
Authors: Declercq Jeroen , Zhu Jingjing , Lindberg Iris , Ghassabeh Gholamreza H. , Meulemans Sandra , Vermorken Alphons J.M. , Van de Ven Wim J.M. , Muyldermans Serge , Creemers John W.M. 
Published: August 2012

Abstract
Furin belongs to a family of seven closely related subtilisin-like serine endoproteases, known as proprotein convertases (PCs), PC1/3, PC2, PC4, PC5/6, PACE4 and PC7. The physiological role of furin is to cleave and hence activate a large variety of proproteins. Therefore, it is not surprising that it plays a major role in many pathologies such as cancer and infectious diseases. Furin inhibition might be a good strategy for therapeutic intervention, and several furin inhibitors have been generated, although thus far none are entirely furin-specific. To reduce potential side effects caused by cross-reactivity with other proteases, dromedary heavy chain antibodies against catalytically active furin were developed as specific furin inhibitors. Nanobodies derived from these antibodies bind only to mouse and human furin but not to other PCs. In addition, upon overexpression in cell lines, these nanobodies can inhibit the cleavage of three different furin substrates, TGFβ, BAFF and GPC3. The purified nanobodies can also inhibit the cleavage of diphtheria toxin into its enzymatically active A fragment, but do not inhibit cleavage of a small synthetic peptide-based substrate, suggesting a mode of action based on steric hindrance. The inhibitory constant of the purified nanobodies was shown to be in the micromolar range and the nanobodies are non-competitive inhibitors as demonstrated by Dixon plot. Furthermore, anti-furin nanobodies can protect HEK293T cells from diphtheria toxin-induced cytotoxicity as efficiently as the well characterized PC inhibitor nona-D-arginine. In conclusion, these antibody-based single-chain nanobodies represent the first generation of highly specific, non-competitive furin inhibitors.
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 4627. doi:1538-7445.AM2012-4627
Abstract 4637: Cell penetrating antibodies for intracellular targets: Expanding the antibody-based treatments for cancer
Authors: Agnes Richard S. , Hitomi Masahiro , Basilion James P. 
Published: August 2012

Abstract
Antibody based therapeutics have gained significant interest in recent years. Herceptin, which targets cell surface protein, have been successful for the treatment of cancer. While antibodies are promising platforms for therapy, antibodies have been limited to targeting cell surface proteins because they cannot penetrate cells. Recently, we have developed cell penetrating antibodies engineered from the conjugation of a cell penetrating peptide (CPP) and an antibody. The CPP-mIgG and CPP-anti-RPA1 IgGs were internalized in cells as observed by fluorescence microscopy. Biological activities of these conjugates were determined and the expected anti-proliferative effects of the CPP-anti-RPA1 were subtly distinguishable from the control CPP-mIgG. While RPA1 is a valid anti-cancer target, its function depends on complicated pathways and cell cycle where dosing may have to be optimized. This demonstrates the difficulties in establishing CPP-IgG as an efficient therapeutic. To demonstrate that CPP-IgG bioconjugates are capable of inducing biological effects, we sought a different intracellular target. Antimitotic drugs are standard cancer chemotherapeutic agents. Recently, other proteins involved in the mitotic machinery have gained much attention. For example, kinesin motor protein Eg5 plays an important role in mitosis and inhibiting Eg5 prevents the formation of bipolar spindles resulting to an unmistakable change of morphology during mitosis_a star-like structure called “monoastral”. Small molecules, such as monastrol and (S)-trityl cysteine (STLC), lead to monastral formation. Thus, we chose Eg5 protein as an intracellular target to demonstrate that CPP-IgG bioconjugates are able to penetrate cells and have neutralizing activity. We expect that CPP-anti-Eg5 conjugates will penetrate cells and produce the canonical inhibition of Eg5 protein by observing for the monoastral morphology during mitosis. We tested whether CPP-anti-Eg5 IgG will present the same biological activity as STLC. We bioconjugated the anti-Eg5 with a CPP. Cell cycle synchronized cells were treated with the positive control STLC and CPP-anti-Eg5 showed an atypical star-like structure similar to monoastral. In whole, these studies show that CPP-IgG against intracellular targets are able to enter the cells and show inhibitory activities. We will describe our progress and discuss approaches to expanding the utility of antibodies as therapeutics for intracellular cancer 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 4637. doi:1538-7445.AM2012-4637
Abstract 4642: Combined glycolytic inhibition and anti-vascular treatment in retinoblastoma: Novel strategy for tumor control avoids chemotherapy
Authors: Murray Timothy G. , Houston Steve , Decatur Christina , Pina Yolanda , Lampidis Ted 
Published: August 2012

Abstract
Purpose: The purpose of this study was to evaluate the combination treatment of glycolytic inhibitors and anti-angiogenic agents on tumor burden and hypoxia in advanced retinoblastoma using the LHbetaTag murine transgenic retinoblastoma model. Methods: Under IACUC protocol, thirty advanced LHbetaTag mice (16 weeks of age) were divided into 5 groups (n=6 per group) and treated with periocular injections of (a) saline, (b) 2-deoxy-glucose (2-DG), (c) anecortave acetate (AA) or (d) 2-DG plus AA (one day post AA treatment) or (e) 2-DG plus AA (one week post AA treatment). Eyes were enucleated at 21 weeks and tumor sections were analyzed for tumor burden and intra-tumoral hypoxia. Results: Combined treatment with 2-DG and AA (both 2-DG one day and one week post AA treatment) showed significant reduction in tumor burden compared to saline control (61% and 56% respectively, p &lt;.001). Eyes treated with 2-DG one day post AA injection showed a significant tumor burden reduction as compared to 2-DG alone or 2-DG plus AA injected after one week (p&lt;01). Further, intra-tumoral hypoxia was eliminated in 2-DG treated eyes at one day post AA injection and was significantly reduced in 2-DG eyes treated one week after AA injection (p&lt;.0001). Conclusion: Combination focal therapy with glycolytic inhibitors and angiogenic inhibitors significantly enhanced tumor control and reduced tumor hypoxia. Treatment timing greatly impacted the effect of combined treatment. Combination therapy with 2-DG and AA was as effective as current chemotherapy regimens in the treatment of LHbetaTag murine transgenic retinoblastoma and may potentially serve as an alternative treatment strategy for advanced pediatric retinoblastoma.
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 4642. doi:1538-7445.AM2012-4642
Abstract 4643: Shedding light on the molecular basis of tumor dormancy using antiangiogenic nanomedicines
Authors: Tiram Galia , Segal Ehud , Bachar Gal , Shreberk Roni , Ofek Paula , Satchi-Fainaro Ronit 
Published: August 2012

Abstract
Based on clinical necessity for improved anticancer drugs and the importance of understanding the mechanism underlying the angiogenic switch phenomenon, we designed a targeted drug delivery system for the treatment of bone-related angiogenesis-dependent malignances. Using multidisciplinary approaches involving novel chemistry and molecular imaging, we synthesized polymer-drug nano-conjugates of HPMA copolymer-alendronate bound to TNP-470 or paclitaxel designed to target the angiogenic switch of bone neoplasms such as osteosarcoma and bone metastases. Antitumor efficacy of the conjugates was evaluated in osteosarcoma- and breast cancer bone metastases-bearing mice revealing improved anti-angiogenic and antitumor activity with reduced toxicity compared with the free drugs. To obtain data regarding the pharmacokinetic profiles of the drugs, we developed a novel prodrug system that enables real-time monitoring of drug release by different fluorescence imaging modalities. To further analyze host-tumor interactions in response to treatment, we developed a model of tumor dormancy based on mCherry-infected human osteosarcoma cells that allows deep tissue signal penetration with an optical readout. This pair of tumor cells that originate from the same parental cell line, enable intravital non-invasive detection of early stages of cancer and evaluation of treatment efficacy with the nanoconjugate. The pair has similar growth rate in vitro. However, when inoculated into mice, Saos-2-E cells established a vascularized and palpable tumor within one month, while Saos-2-D cells remained avascular and non-palpable for a year until they spontaneously escape. Phenotypic and molecular (microRNA-based) differences between these two cell lines were evaluated by in vitro and in vivo methods, with emphasis on changes related to the angiogenesis process. Although slight differences between the Saos-2-D and Saos-2-E cells were shown in vitro, when inoculated in vivo Saos-2-E cells showed increased angiogenic potential compared with the Saos-2-D cells. Our nanoconjugate was able to regress fast growing-angiogenic human tumors to a dormant avascular phenotype.
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 4643. doi:1538-7445.AM2012-4643
Abstract 4655: Aplidin induces a non-canonical ER stress response in HeLa cells response in HeLa cells
Authors: Losada Alejandro , Bejarano Alberto , Palafox Marta , Moreno-Mateos David , Moneo Victoria , Jimenez-Ruiz Antonio , Gago Federico , Cuevas Carmen , Garcia-Fernandez Luis F. , Leal Juan FM , Galmarini Carlos M. 
Published: August 2012

Abstract
Aplidin (APL), a marine cyclic depsipeptide originally found in the Mediterranean tunicate Aplidium albicans, is currently under phase II/III clinical investigation for cancer therapy. The mechanism of action of the compound includes the oxidative-stress mediated activation of Rac1 and JNK1, which rapidly trigger the mitochondrial apoptotic pathway. Comparing the protein expression profiles of HeLa wt cells and an APL-resistant subclone previously generated in our lab (HeLa-APL), we identified a subset of differentially expressed proteins the function of which was related to the unfolded protein response (UPR). HeLa-APL resistant cells showed reduced levels of BiP (GRP78) and relatively higher levels of Ero1α and phospho-eIF2α, indicating a higher basal endoplasmic reticulum (ER) stress. To investigate whether APL was inducing a bona fide ER stress response in HeLa cells and whether this process was essential in the mechanism of action of this compound, we compared the molecular and cellular effects elicited by APL with those induced by two well-known ER-stress inducing agents, thapsigargin and tunicamycin. Basically, while these agents elicited a complete canonical UPR response, APL only triggered part of the stress signaling cascade, including the phosphorylation of eIF2α and JNK1 and a rapid inhibition of protein synthesis. By contrast, CHOP, a transcription factor involved in launching apoptosis by the UPR, was not induced by APL. Rather, it seemed to be slightly reduced in treated cells. Similarly, while tunicamycin induced the alternative splicing of XBP1 by IRE1 and the activation of the ER-related caspase-4, APL failed to induce the same response in HeLa cells. At present, the precise connection between the partial activation of the ER stress signaling pathway and the rapid induction of apoptosis by APL remains poorly understood, although it could represent a new, aberrant UPR response
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 4655. doi:1538-7445.AM2012-4655
Abstract 4660: Antiproliferative effects of antagonists of Inhibitor of Apoptosis Proteins (IAPs) in human cancer cells
Authors: Suh Young-Ah , Lee Gi-Young , Lee Sun-Hae , Bae InHwan , Kim Maeng Sup , Jin Dong-Hoon , Kim Tae Won , Jang Se Jin 
Published: August 2012

Abstract
The inhibitor of apoptosis (IAP) proteins are a family of proteins containing one or more conserved, cysteine and histidine-rich baculoviral IAP repeat (BIR) N-terminal domains and a C-terminal RING domain The BIR domains of the IAPs form the zinc-figure-like structures that bind to active caspases to block caspase activity. The RING domain acts as an ubiquitin ligase to facilitate proteasomal degradation of caspases. Upregulation of IAPs is found in many tumor cell lines as well as in most primary tumor tissues. Increased expression of IAPs has been associated with apoptosis resistance and low sensitivity to chemotherapy drugs in several tumor types. Recent studies have shown that inhibition of levels or functions of survivin and/XIAP with anti-sense, siRNA, and dominant negative mutant survivin genes induces the apoptotic cell death selectively in human tumor cells but not in normal cells. Like such, the importance of IAPs in regulating the apoptotic response and as molecular targets for production of therapeutic effects selectively in tumor cells have attracted a great attention to identify peptide antagonists or small molecule inhibitors for those proteins. In the effort to develop efficient antagonists of IAPs into chemotherapy drug, we analyzed the apoptotic effect of HM antagonists, novel small molecules inhibiting IAP activities, on non-small-cell lung cancer cells and colon cells. We also analyzed changes in cell signaling pathways after HM antagonists treatment to determine the mechanisms of the apoptotic response in cancer cells. Finally, the feasibility of using HM antagonists to sensitize human cancer cells to chemotherapy drugs was examined by combining HM antagonists with two commonly used agents, cisplatin and MK2206. In the present study, we have demonstrated that this reagent efficiently decreased IAPs expression in several NSCLC cells, especially on EGFR activated cells, as well as colon cells. It showed cleaved caspase 3 and PARP, and decreasing phosphor-Akt and phosphor-Erk, indicating that the reagents exerted antiapoptotic activity through inhibition of Akt and MAPK signaling pathways. Ongoing xenograft experiments using NSCLC cells and colon cells would manifest the potential chemotherapeutic agents.
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 4660. doi:1538-7445.AM2012-4660
Abstract 467: Mitochondrial dynamics regulates migration and invasion of breast cancer cells
Authors: Tu Yaping , Zhao Jing , Zhang Juan , Yu Meifang , Wolff Dennis W. , Abel Peter W. 
Published: August 2012

Abstract
Mitochondrial structure is dynamically regulated by fusion and fission events that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found that mitochondria were more fragmented in metastatic breast cancer cells that express higher levels of mitochondrial fission protein dynamin-related protein 1 (Drp1) and less mitochondrial fusion protein 1 (Mfn1). Silence of Drp1 or overexpression of Mfn1 resulted in mitochondria elongation and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silence of Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics had no significant effects on overall mitochondrial bioenergetics but altered the subcellular distribution of mitochondria in breast cancer cells. Silence of Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silence of Mfn proteins caused accumulation of more mitochondria in lamollipodia regions with higher mitochondrial membrane potential, an indication of higher ATP synthesis. Treatment with the ATP uncoupling agent m-chlorophenylhydrazone (CCCP) or mitochondrial ATP synthesis inhibitor oligomycin A caused disappearance of lamellipodia and decreased breast cancer cell migration and invasion. Together, our findings show a new mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting mitochondrial dynamics may provide a novel strategy for suppressing breast cancer metastasis. This work was supported by the National Institutes of Health (CA125661), State of Nebraska Research Fund (Grant LB595), the National Natural Science Foundation of China (31100973) and the National Basic Research Program (2010CB833701, 2012CB934003).
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 467. doi:1538-7445.AM2012-467