bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2526: CP690550 inhibits interleukin-2 (IL-2), IL-9 and IL-15 mediated JAK3 activation and proliferation of T cells obtained from patients with HTLV-1-associated adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP)
Authors: Ju Wei , Zhang Meili , Bryant Bonita R. , Chen Jing , Morris John C. , Janik John E. , Waldmann Thomas A. , Jiang Jian-kang , Thomas Craig J. , Jacobson Steven , Oh Unsong 
Published: February 2011

Abstract
The retrovirus, human T cell lymphotrophic virus-1 (HTLV-1) is the etiologic agent of ATL and the neurological disorder, HAM/TSP. Infection with HTLV-1 results in viral tax protein mediated constitutive activation of the JAK3/STAT5 pathway in patients' T-lymphocytes that is believed to result in malignant transformation or autoimmunity. JAK3 plays a key role in cytokine receptor-mediated signal transduction including the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 that use the common γ- chain. This suggests that inhibitors of JAK3 may be of benefit in HTLV-1-associated diseases. We evaluated the effect of a novel small molecule JAK3 inhibitor, CP690550 on the cytokine-dependent cell line, NK92. CP690550 at 50 or 100 nM effectively inhibited the proliferation of IL-2-stimulated NK92 cells, but not NK92 that were stimulated with IL-12 or the combination of IL-6 and its receptor (IL-6R) that do not utilize the common γ-chain and JAK3 for signaling and proliferation. We also demonstrated the relative specificity of this inhibitor on another cytokine-dependent cell line, 32Dβ where at 50 or 100 nM CP690550 inhibited IL-2 and JAK3 mediated proliferation but did not affect murine IL-3-mediated cell proliferation. The activation mediated phosphorylation of STAT5 in NK92 cells in response to IL-2 stimulation was inhibited by CP690550. We evaluated the action of CP690550 on the ex vivo proliferation of peripheral blood mononuclear cells (PBMC) from selected patients with the smoldering or chronic subtypes of ATL, or HAM/TSP whose PBMC are associated with the production of cytokines, in particular, IL-2, IL-9 and IL-15 that use the common γ-chain and JAK3. CP690550 at 50 nM inhibited the ex vivo spontaneous proliferation of PBMC from 11 patients with ATL and 9 patients with HAM/TSP at 6-day by means of 66% and 86.4%, respectively. CP690550 also inhibited the proliferation of NK92 cells stimulated with the 6-day ex vivo PBMC culture supernatants from ATL and HAM/TSP patients by a mean of 83.9% and 82%, respectively. We also demonstrated that CP690550 effectively inhibited the activation of the JAK3/STAT5 pathway in isolated T-cells from ATL patients. On the basis of this study, the JAK3 inhibitor CP690550 deserve further study as a potential therapeutic agent for select patients with HTLV-1-associated ATL and HAM/TSP.
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 2526.
Abstract 2537: The novel sphingosine kinase inhibitor ABC294640 blocks survival and tumorigenesis in chemo- And endocrine resistant breast cancer
Authors: Antoon James W. , White Martin D. , Gestaut Matthew M. , Slaughter Evelyn M. , Elliott Steven , Driver Jennifer L. , Khalili Hafez S. , Smith Charles D. , Burow Matthew E. , Beckman Barbara S. 
Published: February 2011

Abstract
Resistance to chemotherapy is a major cause of breast cancer treatment failure today. The sphingolipid metabolizing enzyme sphingosine kinase converts pro-apoptotic ceramide into pro-survival sphingosine-1-phosphate (S1P). Sphingosine kinase has been shown to be involved in breast cancer endocrine- and chemo-resistance and is proposed to be a key regulator of proliferation. Here, we studied the effects of the novel sphingosine kinase inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl) amide), on human breast cancer and compared them to its parent compound, SKI-II (4-[[4-(4-Chlorophenyl)-2-thiazolyl]amino]phenol). Treatment with ABC294640 increased levels of endogenous long chain ceramides while simultaneously reducing levels of S1P in vitro. ABC294640 blocked both viability and survival at low micromolar IC50 concentrations in the endocrine therapy resistant - MDA-MB-231, MDA-MB-468 and MDA-MB-361 cells, as well as the chemotherapy resistant MCF-7TN-R cell line. Furthermore, treatment with the inhibitor significantly reduced proliferation, as seen in immunofluorescence staining of Ki-67 in vitro. Interestingly, ABC294640 can induce apoptosis and release caspase-9, possibly through modulation of activity of the transcription factor NF-kappaB. Treatment with 10μM of the inhibitor blocked transcription of genes known to be mediated by the NF-kappaB, such as at IAP1, IAP2, and SOD1. Finally, utilizing xenograft immunocompromised mouse models, ABC294640 significantly reduced breast cancer tumorigenesis of MDA-MB-468 and MCF-7TN-R in vivo. Treatment with 50 mg/kg of the inhibitor for 14 days decreased MDA-MB-468 tumor volume by 37.3% (n=10) compared to vector control. Similarly, there was a 67.4% decrease in tumor volume following 18 days of treatment in the chemoresistant MCF-7TN-R xenograft mice (n=10). These results indicate that pharmacological inhibition of sphingosine kinase with an orally bioavailable selective inhibitor, ABC294640, has therapeutic potential in the treatment of chemo- and endocrine therapy- resistant breast cancer.
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 2537.
Abstract 254: A HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis
Authors: Li Zheng , Zhang Qian , Mao Jian-Hua , Weise Anja , Mrasek Kristin , Fan Xueyu , Zhang Xifeng , Liehr Thomas , Lu Karen H. , Balmain Allan , Cai Wei-Wen 
Published: February 2011

Abstract
There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity (LOH) site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with HDAC1 to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.
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 254.
Abstract 2545: Regulation of NF-YB by miR-485-3p affects TopoisomeraseIIα expression
Authors: Chen Cheng-Fen , Beck William T. , He Xiaolong 
Published: February 2011

Abstract
DNA topoisomerase IIα (TopoIIα) is an essential nuclear enzyme. Our teniposide-resistant human leukemic lymphoblastic cells (CEM/VM-1-5) express reduced TopoIIα protein. To determine the role of TopoIIα in drug resistance, previously we knocked down TopoIIα in parental CEM cells by RNAi. Compared to control cells, CEM-siTopoIIα cells are more resistant to etoposide. Our previous work suggested that the transcription factor NF-YB is a negative regulator of TopoIIα, working through the TopoIIα promoter (Morgan and Beck, Mol. Pharmacol 59:203,2001). We have found that NF-YB protein expression is increased in CEM/VM-1-5 cells compared to CEM cells. This suggests that increased NF-YB may be the cause of reduced TopoIIα in CEM/VM-1-5 cells. We asked what causes the up-regulation of NF-YB in CEM/VM-1-5 cells. MicroRNAs are a recently identified group of non-protein coding RNAs that regulate posttranscriptional gene expression. In our previous study, we found by microRNA profiling that hsa-miR-485-3p, is lower in CEM/VM-1-5 cells compared to CEM cells. MicroRNA target prediction programs also reveal that the 3′ UTR of NF-YB harbors a putative miR-485-3p binding site. We hypothesized that hsa-miR-485-3p regulates drug resistance by decreasing NF-YB expression, which in turn negatively regulates TopoIIα expression. We overexpressed miR-485-3p in CEM/VM-1-5 cells and this led to reduced expression of NF-YB and a corresponding upregulation of TopoIIα. To validate the binding of miR-485-3p to NF-YB 3′-UTR, present experiments with HEK293Tcells using luciferase reporters carrying the 3′-UTR of the NF-YB gene are being done to clarify the role of miR-485-3p in this phenomenon. (Supported in part by CA40570 from NCI and in part by UIC)
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 2545.
Abstract 2580: Single-chain antibody based immunotoxins targeting Her2/neu: design optimization and impact of affinity on antitumor effects
Authors: Cao Yu , Marks James D. , Hittelman Walter N. , Adams Gregory P. , Simmons Heidi H. , Cheung Lawrence H. , Rosenblum Michael G. 
Published: February 2011

Abstract
Recombinant immunotoxins, consisting of single-chain antibodies (scFv) genetically fused to polypeptide toxins represent potentially effective candidates for cancer therapeutics. Antibody affinity, internalization rates and intracellular fate of molecular constructs play critical roles in the eventual cytotoxic activities of these constructs although these events related to the design characteristics of fusion constructs have not been comprehensively explored. We evaluated the relationship between affinity of various anti-Her2 scFv fused to recombinant gelonin (rGel) and its effect on cytotoxic activity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3.9, MH3B1 and B1D3-in increasing affinity order). The affinities of the scFv ranged from 10−8 to 10−11 M and the rGel fusion toxins retained the affinities of the scFv from which they were derived. Against BT474M1 human breast tumor cells, the immunotoxins demonstrated IC50 values of 18.9, 10.9, 3.9 and 1.2nM for the C6.5, ML3.9, MH3B1 and B1D3 based immunotoxins respectively. Targeting indices were highest for the B1D3/rGel construct with the highest affinity. The internalization rate of the fusion constructs into target cells directly correlated with the cytotoxic effects. Competition studies showed that addition of soluble Her2/neu extracellular domain (ECD) as the competitive factor significantly reduced the cytotoxic effects of the highest-affinity fusion construct (B1D3/rGel) while the lower-affinity constructs showed lesser impact of Her2/neu ECD addition on the cytotoxic effect. Animal model efficacy studies against several Her2/neu overexpressing tumors are ongoing but appear to suggest that the construct containing the highest affinity antibody was comparatively less effective in vivo than constructs containing antibodies of intermediate affinity. These studies suggest that human MH3B1/rGel fusion construct with an apparent affinity of 10−10 M displayed an overall optimal cell-killing activity to several Her2/neu positive cancer cells especially in the presence of free Her2/neu ECD. These findings demonstrate the necessity to consider antibody affinity in design considerations for targeted therapeutics. In addition, the potential impact of soluble target or truncated receptor molecules in the environment need to be considered when evaluating the efficacy of targeted therapeutics. Research Conducted, in part, by the Clayton Foundation for Research.
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 2580.
Abstract 2582: Branched neurotensin peptides for the selective targeting of human colon and pancreas carcinoma
Authors: Bracci Luisa , Falciani Chiara , Lelli Barbara , Brunetti Jlenia , Lozzi Luisa , Pini Alessandro , Pagliuca Chiara , Ravenni Niccolò , Bencini Lapo , Menichetti Stefano , Moretti Renato 
Published: February 2011

Abstract
The aim of this study was to validate oligo-branched peptides as selective targeting agents that might be effective either for spotlighting tumor cells that over-express peptide receptors, or for killing them, simply by exchanging the functional moiety coupled to the conserved receptor-targeting core. Tetra-branched peptides containing neurotensin (NT) sequence are described here for selective targeting of human colon, pancreas and prostate cancer. Fluorophore-conjugated peptides were used to measure tumor versus healthy tissue binding in human surgical samples, resulting in validation of neurotensin receptors as highly promising tumor-biomarkers. Drug-armed branched peptides were synthesized with different conjugation methods, resulting in uncleavable adducts or drug-releasing molecules. Cytotoxicity on human cell lines from colon (HT-29), pancreas (PANC-1) or prostate (PC-3) carcinoma indicated branched NT conjugated with MTX and 5-FdU as the most active agents on PANC-1 (EC50 4.4e-007 M) and HT-29 (1.1e-007 M), respectively. Tetra-branched NT armed with 5-FdU was used for in vivo experiments in HT-29-xenografted mice and produced a 50% reduction in tumor growth with respect to animals treated with the same amount of free drug. An unrelated branched peptide carrying the same drug was completely ineffective. In vitro and in vivo results indicated that branched peptides are valuable new tools for tumor selective targeting.
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 2582.
Abstract 2589: Robust in vitro anti-tumor activity of Trastuzamab antibody drug conjugates in HER2 amplified cell lines
Authors: Mohan Sankar , O'Brien Carol , Savage Heidi , Phillips Gail , Lackner Mark , Pandita Ajay 
Published: February 2011

Abstract
Breast cancer is a heterogeneous disease with molecular subtypes characterized by distinct gene expression signatures and histopathology. The defining characteristic of the HER2-amplified subtype is high-level amplification of the HER2 oncogene and overexpression of HER2 protein. Assays for protein overexpression and chromosomal amplification are currently used as diagnostic markers to select patients for HER2-targeting therapies. In the current study, we compared the sensitivity of several HER2-targeting therapies across a panel of 31 breast cancer cell lines and correlated the sensitivity of the cell lines with HER2 positivity detected by IHC, qPCR and FISH. The agents used in screening were trastuzamab, two antibody-drug conjugates (ADCs) consisting of trastuzamab conjugated to an anti-mitotic agent, and a small molecule inhibitor of HER2 kinase activity. HER2 testing revealed 32% of the cell lines to be positive for HER2 by qPCR and FISH, and 90% of these demonstrated a high-level amplification as demonstrated by HER2 amplifications in the form of clusters by FISH and more than 10 copies by qPCR. Several of the cell lines showed polysomy for chromosome 17 and extra copies of HER2 by FISH assay but did not meet the criteria for HER2 amplification. The HER2 IHC assay showed 10 cell lines to be positive (2+, 3+) by IHC, with 8 illustrating high-level expression (3+). The agents tested were more efficacious in the HER2-amplified cell lines, with the broadest activity observed in response to the ADCs. Cell lines exhibiting polysomy for HER2 and 1+ expression by IHC were less responsive to any of the agents tested. Consistent with previous reports, many of the cell lines resistant to trastuzamab or the small molecule HER2 inhibitor demonstrated deregulation of the PI3K pathway illustrated by mutations in the PIK3CA gene or loss of PTEN protein expression. Interestingly, the majority of these resistant cell lines were sensitive to ADCs. In summary, our study illustrates a high sensitivity of ADCs in breast cancer cell lines harboring a high-level amplification of the HER2 gene and suggests these agents may overcome in vitro resistance provided by activation of the PI3K pathway.
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 2589.
Abstract 259: Functional analysis of the β1 subunit of AMP-activated protein kinase in ovarian cancer
Authors: Li Cuilan , Liu Vincent W. S. , Chan David W. , Ngan Hextan Y. S. 
Published: February 2011

Abstract
AMP-activated protein kinase (AMPK) is a heterotrimer composed of a catalytic subunit (α) and two regulatory subunits (β and γ). Each subunit has different isoforms, namely, α1, α2, β1, β2, γ1, γ2 and γ3 encoded by distinct genes, which enable the yielding of 12 possible heterotrimeric complexes. Originally known as a cellular energy-balancing sensor, AMPK was recently found to have strong tumour suppression function. Roles of AMPK have recently been extensively studied in metabolic diseases and human cancers. However, the functional aspects of individual subunits of AMPK are barely investigated. Using quantitative RT-PCR, we found that the AMPK-β1 subunit was over-expressed in ovarian cancer as compared with normal ovary. Over-expression of the AMPK-β1 was further confirmed by immunohistochemical staining (IHC) of the paraffin-embedded ovarian tissues. Clinicopathological data analysis indicates that over-expression of AMPK-β1 correlates with low-grade tumour. Furthermore, from the IHC, the geographical location of the AMPK-β1 in ovarian cancer tissues was also known. In addition to its appearance in the cytoplasm, the AMPK-β1 is also presence in the cell membrane. Since the active form of AMPK (phospho-AMPK) only locates at the cytoplasm, we postulate that AMPK-β1 has addition functions other than just component of the AMPK molecule. To determine the role of AMPK-β1 in ovarian cancer, we have carried out functional analysis of the expression of AMPK-β1 in ovarian cancer. Interestingly, AMPK-β1 was found to inhibit cell growth when forced expressed in ovarian cancer cells. Enforced expression of AMPK-β1 can activate AMPK or down-regulate the level of phospho-AKT in ovarian cancer cells. Additional assays are being studied to further determine the role of AMPK-β1 in ovarian cancer. Understanding the functional role of AMPK-β1 may facilitate the design and development of a new strategy for therapeutic intervention.
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 259.
Abstract 2590: Preclinical evaluation of ASG-5ME, a novel antibody-drug conjugate for pancreatic cancer
Authors: Smith Leia M. , Gudas Jean M. , Lewis Tim , Duniho Steve , An Zili , Morrison Kendall , Jia Xia C. , Raitano Art B. , Moser Ruth , Lyon Robert P. , Hayes Dawn , Senter Peter D. , Jakobovits Aya , Benjamin Dennis R. 
Published: February 2011

Abstract
Antibody-drug conjugates (ADCs) have demonstrated promising activity and tolerability profiles in oncology clinical trials, including for Hodgkin lymphoma (brentuzumab vedotin) and breast cancer (trastuzumab-DM1), motivating the development of new ADCs targeting antigens in other prevalent cancers. An immunohistochemical survey of expression of the novel tumor antigen AGS-5 revealed strong staining in 90% of pancreatic cancer specimens tested. Importantly, this staining was largely uniform, with essentially all transformed cells demonstrating membranous staining. This observation along with the observation of equally abundant expression of AGS-5 in prostate and other cancers motivated the development of ASG-5ME, an ADC targeting AGS-5. The ADC is comprised of a fully human IgG2 monoclonal antibody conjugated to the potent tubulin-binding drug monomethylauristatin E, conjugated with an average of 3.7 drug molecules per antibody. Conjugation and analysis of this IgG2 ADC will be discussed. The resulting conjugate demonstrated antigen-dependent internalization and in vitro cytotoxicity at sub-saturating ADC concentrations, as well as potent in vivo antitumor activity in patient-derived xenograft models of pancreatic cancer. ASG-5ME has a long (12 day) T1/2 in mice. Taken together, these results support the clinical evaluation of ASG-5ME for treatment of pancreatic cancer
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 2590.