bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-37: Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling
Authors: Wey Shiuan , Luo Biquan , Ni Min , Zhou Hui , Fu Yong , Bhojwani Deepa , Carroll William L. , Lee Amy S. 
Published: August 2014

Abstract
Traditionally GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors, thus, its role in hematologic malignancies remains to be determined. In this study, elevated GRP78 expression was detected in leukemic blasts of adult patients, leukemia cell lines and inversely correlates with time to relapse in childhood acute lymphocytic leukemia. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell (HSC) population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null bone marrow cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of AKT phosphorylation by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through control of oncogenic AKT/mTOR signaling. Furthermore, overexpression of GRP78 renders human leukemic cells more resistant to AraC-induced apoptosis whereas knockdown of GRP78 sensitizes them, suggesting GRP78 is a novel potent therapeutic target for leukemia.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-37. doi:10.1158/1538-7445.AM2011-LB-37
Abstract LB-379: Combating trastuzumab resistance by targeting Src, a common node downstream of multiple resistance pathways
Authors: Zhang Siyuan , Huang Wen-Chien , Li Ping , Guo Hua , Poh Say-Bee , Brady Samuel , Xiong Yan , Tseng Ling-Ming , Li Shau-Hsuan , Ding Zhaoxi , Sahin Aysegul , Esteva Francisco , Hortobagyi Gabriel , Yu Dihua 
Published: August 2014

Abstract
Objective of the study: Trastuzumab is a highly successful example of rationally designed ERBB2-targeted therapy. However, about half of patients with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies due to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. The objective of the study is to find a common key node of multiple trastuzumab resistance mechanisms and design a clinical applicable strategy to target this common node to more effectively overcome trastuzumab resistance. Methodology: First, we evaluated Src activity in multiple acquired and de novo trastuzumab-resistant cell lines models. Cells with modulated Src activity were examined for trastuzumab resistance in vitro and in an orthotopic xenograft model. Moreover, tumors from patients receiving trastuzumab therapy were also analyzed retrospectively for clinical correlation of Src activity with trastuzumab response. Src activated trastuzumab-resistant cells were further treated with Src inhibitor (saracatinib), trastuzumab, or a combination of both in vitro and in vivo. Results: We demonstrate that the non-receptor tyrosine kinase Src serves as a critical modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. Src is activated in both acquired and de novo trastuzumab-resistant cells. Increased Src activation conferred significant trastuzumab resistance (P = 0.011) in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting the common node Src in combination with trastuzumab universally sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo. Targeting Src, a critical convergence point of divergent trastuzumab resistance mechanisms, represents a highly effective and clinically convenient strategy to overcome trastuzumab resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-379. doi:10.1158/1538-7445.AM2011-LB-379
Abstract LB-38: Selective Smoothened antagonists for anti-tumor therapy
Authors: Tunici Patrizia , Mancuso Mariateresa , Giordano Cinzia , Ferruzzi Pietro , Mennillo Federica , Tanori Mirella , Saran Anna , Thomas Russell ,   Gal. La Pericot Mohr, Bakker Annette 
Published: August 2014

Abstract
The Hedgehog (Hh) pathway is an important signaling pathway during cellular proliferation, differentiation and embryonic morphogenesis. Aberrant pathway activation has been linked to tumorigenesis in several cancers, (including pancreatic, prostate, lung, colorectal, bladder and ovarian) and therefore the inhibition of the pathway could be an attractive approach for anticancer therapy. The pathway is either activated by the binding of one of the three Hh ligands (sonic, Indian and desert) to the Patched transmembrane protein or by the mutation of inhibitory pathway components (e.g. Pached, SUFU,…). Pathway activation by ligand binding to Patched releases patched repression of the smoothened (Smo) receptor. Activated Smo initiates a cascade of events leading to the activation of transcription factors of the Gli family. Pathway activation by mutation has been reported in diseases such as medulloblastoma or basal cell carcinoma in which the Patched co-receptor is mutated, thereby functionally inactivated and unable to repress the Smo receptor. We report the characterization of a novel Smoothened receptor antagonist (SEN450), showing Hedgehog pathway specific activity in hedgehog responsive cellular models. Finally, we show a synergistic effect of SEN450 with temozolomide in a subcutaneous CD-1 nude mice xenograft of DBTRG-05MG neurospheres. Our data indicate that growing conditions can affect hedgehog responsive cells and that a combined therapy with temozolomide and hedgehog inhibitors could be helpful in the prevention/delay of GBM recurrence. Moreover, we have obtained extremely promising in vivo data using two compounds structurally related to SEN450 in a xenograft tumour model that have been generated from irradiated heterozygous Patched mice. In the current study, the Ptc+/− mice were used to generate a tumor model by transplanting medulloblatoma fragments subcutaneously in nude mice. Upon tumor development two Smo antagonists administered orally were tested in this model. Both compounds showed a significant reduction in tumor volume that was maintained over the entire dosing period. Histological examination showed very low mitotic index in treated tumors versus controls. The expression of the target gene Gli1 revealed a significant decrease of the gene expression in treated samples. The results corroborated the specificity of action of both molecules in targeting the Hh pathway always activated in this tumor model. Further investigation is in progress in order to verify the antitumor capacity of the compounds in other tumor models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-38. doi:10.1158/1538-7445.AM2011-LB-38
Abstract LB-382: Inhibition of CD95 signalling by APG-101 enhances efficacy of radiotherapy (RT) and reduces RT-induced tumor satellite formation
Authors: Pfenning Philipp N. , Weiler Markus , Merz Christian , Jugold Manfred , Gieffers Christian , Platten Michael , Fricke Harald , Wick Wolfgang 
Published: August 2014

Abstract
CD95 is a prototype death receptor that regulates the induction of apoptosis, upon binding of its ligand CD95L. Therefore, activation of the CD95L/CD95 system has been regarded an excellent target for treatment of various malignancies. In contrast to the aim of promoting CD95 activation, there is compelling evidence that CD95 is able to promote tumor growth through intracellular non-apoptotic signalling mechanisms. This mechanism has recently been described for glioblastoma, in which activation of CD95 by CD95L leads to invasive growth and glioma cell migration. This is signalled through increased activity of pivotal glioblastoma invasion-related proteases, that is matrix metalloproteinases (MMP). With this shift of paradigms, blocking of the CD95L mediated invasion of tumor cells and subsequent tumor progression may therefore be a promising approach in anti-glioma therapy. APG101 is a fusion protein, consisting of the extracellular domain of human CD95 and the Fc-region of human immunoglobulin G. Hence, it acts as a soluble CD95 receptor trapping the CD95 ligand.
The presented project aims at analyzing the clinical relevance of blocking CD95 signalling, given the fact that glioma patients with upregulated CD95 expression have worse survival rates than those with intermediate expression levels. In proof-of principle experiments APG101 inhibits CD95L-mediated invasion of glioma cells. More importantly, APG101-treatment (100 mg/kg body weight) resulted in significantly prolonged survival of SMA560-tumor bearing Vm/Dk mice, less glioma cell satellites in the surrounding tissue and reduced activity of MMP. APG101 in combination with focal irradiation at 6 Gy demonstrated a remarkable reduction of tumor growth with a significantly prolonged survival compared with irradiation treatment alone and inhibition of the proinvasive properties of radiotherapy as demonstrated by magnetic resonance imaging and histology. Surprisingly, APG-101 added to the vascular endothelial growth factor receptor (VEGFR) inhibitor cediranib (AZD2171) did not increase the survival of SMA-560-tumor bearing mice as compared to cediranib alone nor did it impair the proinvasive consequences of cediranib.
Our data strongly support the potential use and clinical evaluation of APG101 in combination with radiotherapy in the treatment of malignant glioma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-382. doi:10.1158/1538-7445.AM2011-LB-382
Abstract LB-39: Phenotypic switching and molecular anatomy of malignant progression (E-M-T/M-E-T).
Authors: Gao Chong-Feng , Vande woude George F. 
Published: August 2014

Abstract
Proliferation and invasion are two fundamental phenotypes required for malignancy while phenotypic switching is required for malignant progression. Thus, during malignant progression primary tumor cells switch from proliferative to invasive phenotypes and switch again to form proliferating metastases. The acquisition of the invasive phenotype through epithelial-mesenchymal-transition (E-M-T) is a crucial step in tumor progression, as is mesenchymal-epithelial-transition (M-E-T) or switching to become tumor metastases. Using a reductionist approach, we have been able to reproduce these steps through a combination of in vitro and in vivo methods: Beginning with prostate and ovarian carcinoma cells, we show that the majority are epithelial (E) cells, grow as acini in three dimensional (3D) Matrigel and are nonresponsive to hepatocyte growth factor/scatter factor (HGF/SF). These E cells grow in soft agar and are tumorigenic in immunocompromised mice. However, there is a second cell population which also grows as acini in 3D Matrigel, but display extensive branching morphogenesis when HGF/SF is present. These subclones are mesenchymal (M), are highly invasive in response to HGF/SF, but do not grow in soft agar and display low or no tumorigenicity in vivo. We show that M cells can originate in vitro from the non-invasive E subclones. However, M subclones undergo M-E-T only in vivo, at low frequency mimicking tumor progression to proliferating metastases.
We show that E-M-T switching events occur with loss of E-Cadherin and the gain of c-MET expression. Expression of β-Catenin does not change with phenotypic switching, but with the loss of E-Cadherin, its localization shifts from the cell membrane to nuclear/cytoplasmic location, activating β-Catenin dependent expression. Moreover, depleting E-Cadherin in E cells triggers nuclear/cytoplasmic shift of β-Catenin and enhanced HGF/SF-c-Met signaling, while ectopic expression of E-Cadherin in M cells restores E phenotype and decreases HGF/SF-Met signaling. Importantly, we show that phenotypic switching occurs with distinct changes in karyotype that dictate changes in the chromosome transcriptome and the expression of genes that account for changes to M or to E phenotypes, thereby implicating chromosome instability as a key mechanism for phenotypic switching. We conclude that chromosome instability generates the transcriptome diversity in vitro or in vivo, which in the appropriate environment, leads to expansion of clonal variants responsible for phenotypic switching.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-39. doi:10.1158/1538-7445.AM2011-LB-39
Abstract LB-391: Aurora kinase inhibitor AT9283 potently inhibits the proliferation and migration of medulloblastoma cells
Authors: Macdonald Tobey J. , Liu Jingbo , Lyons John 
Published: August 2014

Abstract
Aurora kinases play an important role in regulating cell mitotic division. It has been found that they are over expressed in many human cancers, and decreased expression in either Aurora kinase A or B levels lead to cell apoptosis. It has been suggested that Aurora kinase inhibitors might be an attractive molecular target of anticancer therapy. AT9283, a multi-targeted kinase inhibitor with potent activity against both Aurora kinases A and B, is currently being evaluated in clinical trails in patients with advanced hematological malignancies including AML. However to date, this compound has not been evaluated in medulloblastoma, one of the most common malignant brain tumors in children. In this study, AT9283 was investigated in a panel of human medulloblastoma cell lines (DAOY and D556) and the SmoA1 transgenic mouse model of medulloblastoma cells (PS125) to assess its ability to inhibit medulloblastoma cell survival, growth and migration. Western blotting demonstrated significant inhibition of both Aurora kinases A and B in each cell type by AT9283. MTT assay demonstrated that AT9283 significantly inhibited cell growth and proliferation in a dose-dependent manner in all 3 cell lines. Furthermore, the compound potently reduced phospho-histone H3 levels, and induced caspase-3 and cleaved PARP in all cells. AT9283 treatment at concentrations as low as 0.01–0.05μM significantly inhibited cell migration, as demonstrated by the Scratch assay without affecting caspase-3 induction, cleaved PARP or phospho-histone H3 levels. Thus taken together, our results indicate that AT983 has a dual effect on inhibiting cell growth and migration in medulloblastoma cells, suggesting it may be a valuable therapy in medulloblastoma treatment and warrants further preclinical in vivo investigation in this disease model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-391. doi:10.1158/1538-7445.AM2011-LB-391
Abstract LB-396: FGFR4-antagonistic CovX-Body™ inhibits tumor growth
Authors: Kaspar Allan A. , Liu Dingguo , Do Janet , Betancourt Oscar , Liu Bin , Desharnais Joel , Del Rosario Joselyn , Li Lingna , Pirie-Shepherd Steven , Levin Nancy , Bhat Abhijit , Woodnutt Gary , Lappe Rodney 
Published: August 2014

Abstract
FGFR4 is the receptor for FGF19. Published data has shown FGF19 transgenic animals develop hepatocellular carcinoma (HCC), suggesting that the FGFR4:FGF19 axis may play a role in HCC. FGFR4 upregulation has been shown to be a negative prognostic indicator in multiple tumor types.
CVX-63, an FGFR4-specific CovX-Body, was produced by fusing a chemically modified peptide to the specific Fab binding site of a specially designed antibody. CVX-63 was shown to inhibit FGF19 binding to FGFR4 in a competition ELISA with an IC50 of 10 nM, and had no cross reactivity with FGFR1–3.
CVX-63 has a beta half life of 55 hrs in the mouse. The anti-tumor activity of CVX-63 was demonstrated in a staged Colo-205 xenograft model, with CVX-63 administered i.v. weekly. Maximal activity of 30% tumor growth inhibition was seen at dosing 10 mg/kg. Immunohistochemistry analysis of treated tumors shows a &gt;90% reduction in phospho-ERK and 50% downregulation of FGFR4 on tumor cells. Ki67, a marker of proliferation was reduced, but active caspase 3 was not found in treated tumors.
A patient-derived HCC xenograft was identified which expresses both FGFR4 and FGF19. When tested in this HCC model, CVX-63 did not show any effect inhibiting tumor growth. These data demonstrate that CVX-63 effectively inhibits FGFR4 activity in xenografts. FGFR4 inhibition has a modest effect on human tumor progression and FGFR4 does not seem to be a critical driver of HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-396. doi:10.1158/1538-7445.AM2011-LB-396
Abstract LB-400: STAT3 mediates resistance to MEK inhibitor through microRNA miR-17
Authors: Dai Bingbing , Meng Jieru , Peyton Michael , Girard Luc , Bornmann William G. , Ji Lin , Minna John D. , Fang Bingliang , Roth Jack A. 
Published: August 2014

Abstract
AZD6244 is a small-molecule-based inhibitor targeting the MEK pathway that is currently in clinical trials. However, the mechanisms mediating intrinsic resistance to MEK inhibition remain to be completely characterized. To identify the molecular mechanism of MEK inhibitor resistance, we analyzed responses of 38 lung cancer cell lines following AZD6244 treatment and their genome-wide gene expression profiles and identified a panel of genes correlated with sensitivity or resistance to AZD6244 treatment. Ingenuity pathway analysis revealed that activation of the signal transducer and activator of transcription 3 (STAT3) pathway was associated with MEK inhibitor resistance. Inhibition of the STAT3 pathway using JSI-124, a STAT3-specific inhibitor, sensitized lung cancer cells to AZD6244 treatment and induced apoptosis in vitro and in vivo. Moreover, combining a STAT3 inhibitor with AZD6244 induced the expression of BIM and poly (ADP-ribose) polymerase (PARP) cleavage, whereas activation of the STAT3 pathway inhibited BIM expression and thus induced MEK inhibitor resistance. In addition, we found that miR-17, which is regulated by STAT3, played an important role in STAT3-mediated MEK inhibitor resistance by targeting BIM. Inhibition of miR-17 with anti-miR-17 sensitized resistant cells to AZD6244 by inducing BIM and PARP cleavage. We conclude that STAT3-mediated overexpression of miR-17 blocked BIM expression, which resulted in resistance to AZD6244. These results implicate novel alternative approaches for overcoming the MEK inhibitor resistance by combining AZD6244 with STAT3 inhibitors or miR-17 antagomirs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-400. doi:10.1158/1538-7445.AM2011-LB-400
Abstract LB-42: Inducible mouse models for studying liver stem cell activation and tumor development
Authors: Endo Yoko , Zhang Mingjun , Yamaji Sachie , CANG YONG 
Published: August 2014

Abstract
In contrast to skin and intestine, liver does not undergo constant renewal, but it can regenerate itself after massive damage or volume loss. Liver regeneration is driven by proliferation of parenchymal hepatocytes, but when hepatocyte proliferation is compromised, quiescent liver stem cells (LSCs) can be activated to differentiate to transit-amplifying oval cells and eventually to hepatocytes and cholangiocytes. Currently no specific biomarkers have been defined for LSCs, making it difficult to characterize this rare population of cells. Conventional rodent models, i.e., mice or rats treated with liver damaging chemicals followed by partial hepatectomy, are not ideal for studying LSCs due to the promiscuous toxicity of the chemicals and the lack of distinguishing damaged and non-damaged cells.
Here we demonstrate that hepatocyte-specific deletion of Damaged DNA Binding protein 1 (DDB1), an E3 ubiqutin ligase required for cell cycle progression targeted by oncogenic hepatic B virus X protein, abolishes self-renewal capacity of hepatocytes. This defect leads to compensatory activation of DDB1-expressing and EpCam-positive oval cells. These DDB1 mutant mice exhibit very minor liver damage, compared with mice that are treated with diethyldithiocarbamate (DDC). These EpCam-positive oval cells, purified by fluorescent-activated cell sorting, express both hepatotcyte and cholangiocyte markers, can form colonies in vitro, and differentiate to hepatocytes after transplantation. Microarray analysis was performed to compare gene expression profiles in EpCam-positive cells isolated from DDB1 mutant mice and from DDC-treated mice. Several previously unrecognized genes are found to be specifically upregulated in DDB1 mutant mice. LGR5, a stem cell marker found in intestine, colon, stomach, and hair follicles, is demonstrated to be not expressed in facultative LSCs or oval cells in both our genetic models and DDC models. Interestingly, DDB1 mutant mice develop liver tumors in an age-dependent manner, and the onset of tumorigenesis is positively correlated to the extent of LSC activation. We are currently investigating the possible origin of these tumors from activated LSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-42. doi:10.1158/1538-7445.AM2011-LB-42