bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-283: JX-594, a targeted multi-mechanistic oncolytic poxvirus, selectively infects tumor vasculature and causes acute tumor vascular disruption and necrosis in advanced cancer patients
Authors: Breitbach Caroline , Arulanandam Rozanne , Patt Richard , De Silva Naomi , Parato Kelley , Daneshmand Manijeh , Hickman Theresa , Bell John C. , Kirn David H. 
Published: August 2014

Abstract
JX-594 is a first-in-class targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and epidermal growth factor receptor (EGFR)/ras pathway activation. Direct oncolysis plus granulocyte macrophage -colony stimulating factor (GM-CSF) expression also stimulates anti-tumoral immunity. JX-594 infection was evaluated in vitro on human umbilical vein endothelial cells (HUVECs) and by immunohistochemical analysis in tumor biopsies from JX-594 treated (intravenous administration) patients with advanced, treatment-refractory solid tumors. JX-594 associated changes in tumor perfusion were also assessed in patients by dynamic contrast-enhanced magnetic resonance imaging (dce-MRI; at baseline and Day 5 after intratumoral JX-594 administration). In vitro susceptibility of HUVECs to JX-594 infection was shown to be dependent on vascular endothelial growth factor (VEGF) stimulation. Furthermore, JX-594 was capable of infecting tumor-associated endothelial cells after intravenous infusion in patients with advanced solid tumors. No clinical evidence of normal vasculature infection or toxicity was noted. Tumor perfusion was significantly decreased within 5 days post JX-594 treatment, including in hepatocellular carcinoma and colorectal cancer metastases. Perfusion was markedly reduced in both directly injected and distant non-injected tumors. Choi (necrotic) responses at later timepoints were demonstrated. In addition to targeting cancers by direct infection and lysis of tumor cells, JX-594 is capable of directly infecting VEGF-stimulated/tumor-associated endothelial cells. By targeting tumor-associated vasculature, JX-594 acutely disrupts the tumor's blood supply leading to tumor destruction. Targeted oncolytic poxviruses such as JX-594 represent a novel and highly selective class of vascular disrupting agents.
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-283. doi:10.1158/1538-7445.AM2011-LB-283
Abstract LB-290: Glycogen synthase kinase-3β inhibits tumor growth and angiogenesis of gastric cancer
Authors: Ko Young San , Cho Sung Jin , Yoon Jiyeon , Chang Mee Soo , Lee Byung Lan 
Published: August 2014

Abstract
Objective: The mechanisms underlying angiogenesis in cancer are diverse. Although in vitro studies have shown that glycogen synthase kinase-3β (GSK-3β) inhibits the expressions of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in several cancer cells, the implication of GSK-3β in cancer angiogenesis in vivo has not been shown. We examined the effects of GSK-3β on angiogenesis and human gastric cancer growth.
Methods: Human gastric cancer cell lines SNU-638 and SNU-484 were stably transfected with either human wild-type (WT)-GSK-3β or kinase-dead (KD)-GSK-3β, and the effects of GSK-3β on tumor growth and angiogenesis were examined in in vivo experiments. Gastric cancer cells were injected into nude mice subcutaneously and the size of xenografted tumors was measured. The effects of GSK-3β inhibition on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, Western blotting and semiquantitative reverse transcription-polymerase chain reaction. In addition, GSK-3β effects on the HIF-1α degradation and synthesis were examined.
Results: Xenografts in nude mice derived from stable gastric cell lines over-expressing KD-GSK-3β showed larger tumor volumes and higher microvessel density than those over-expressing WT-GSK-3β. Immunohistochemistry and Western blot analysis using xenografted tumor tissues showed that KD-GSK-3β over-expression increased immunoreactivity for Ki-67, HIF-1α, VEGF or CD31 compared with WT-GSK-3β over-expression. In addition, KD-GSK-3β over-expression enhanced HIF-1α expression under hypoxic conditions at the translational level, but not under normoxic conditions.
Conclusion: These results indicate that GSK-3β inhibits gastric tumor growth and angiogenesis by regulating the expression of HIF-1α and VEGF in gastric cancer cells under hypoxic conditions. Our results suggest the potential usefulness of GSK-3β/HIF-1α/VEGF pathway to find molecular targets in gastric cancer.
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-290. doi:10.1158/1538-7445.AM2011-LB-290
Abstract LB-295: Combination of PI3K (SAR245408 and SAR245409) and MEK (MSC1936369B) inhibitors induce tumor apoptosis in vivo: fluorescence molecular tomography study in a human colon carcinoma xenograft model
Authors: GUERIF Stephane , D'heilly Sebastien , Lefranc Celine , Egile Coumaran , Debusshe Laurent , Vincent Loïc , Carrez Chantal , Chiron Marielle , Ma Jiango , Ogden Janet A. , Lager Joanne , Garcia-Echeverria Carlos , Lengauer Christoph 
Published: August 2014

Abstract
The Merck-Serono MEK1/2 allosteric inhibitor MSC1936369B (formerly known as AS703026) was combined with the sanofi-aventis pan-PI3K inhibitor SAR245408 (also known as XL147) or the pan-PI3K/mTOR inhibitor SAR24540 (also know as XL765) in mice bearing colon carcinoma HCT116 xenograft tumors. These tumors harbor both KRAS (G13D) and PIK3CA (H1047R) mutations. Apoptosis induction was monitored non-invasively in vivo using fluorescence molecular tomography (FMT) after injection of fluorescent Annexin-V. Ex vivo apoptosis was assessed on tumor lysates using assays for cleaved caspase-3 and cleaved PARP detection.
Suboptimal doses of SAR245408, SAR245409, and MSC1936369B were administered orally on a daily schedule as single agents or in combination. Single agent treatments showed marginal or no activity on HCT116 tumor growth inhibition. In contrast, robust enhanced anti-tumor activity was observed with the combination treatments, resulting in sustained tumor stasis and regression for both SAR245408/MSC1936369B (p&lt;0.0001) and SAR245409/MSC1936369B (p=0.0009) combination regimens. This therapeutic synergy was associated with clear induction of tumor apoptosis after four days of treatment, as evidenced by markedly increased levels of cleaved caspase-3 and cleaved PARP proteins in the tumor lysates. Apoptosis monitored in vivo by FMT was induced for the SAR245408/MSC1936369B combination, with p=0.005 and p&lt;0.0001 after three and seven days of therapy respectively.
In conclusion, the combination between the MEK1/2 inhibitor MSC1936369B with the pan-PI3K inhibitor SAR245408 or the pan-PI3K/mTOR SAR245409 resulted in significantly enhanced anti-tumor activity in a KRAS/PIK3CA mutated tumor xenograft model, with synergistic induction of tumor apoptosis as demonstrated ex vivo for both combinations and in vivo using longitudinal FMT imaging for the SAR245408/MSC1936369B combination.
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-295. doi:10.1158/1538-7445.AM2011-LB-295
Abstract LB-296: Involvement of T-cell immunity in changes in the plasma amino acid profiles of patients with colorectal cancer
Authors: Ohara Eiji , Kitadai Yasuhiko , Shinagawa Kei , Sumida Tomonori , Tanaka Miwako , Ohnishi Mayu , Nagai Kenta , Ueno Yoshitaka , Tanaka Shinji , Fujii Kiyomu , Nakamura Kazuki , Yoneda Junya , Chayama Kazuaki 
Published: August 2014

Abstract
Metabolic changes in patients with various disorders, including liver disease and cancer, lead to alterations in amino acid balance, and plasma amino acid profiles can be used to discriminate between non-malnourished patients with cancer and healthy individuals. Not with standing, the mechanisms of amino acid imbalance are not well understood. In patients with cancer, various factors including metabolic changes in the tumor itself and immune responses may affect plasma amino acid levels. To investigate involvement of the immune system, we measured plasma amino acid levels in an orthotopic transplant model of colon cancer established in both conventional BALB/c mice and athymic BALB/c nude mice (T-lymphocyte-deficient mice).
CT26 colon cancer cells (murine colon cancer cell line) were implanted into the cecal wall of the BALB/c mice (n=10) and nude mice (n=10). Plasma samples were collected from the tumor-bearing mice at 7 and 14 days after transplantation, and changes in plasma amino acid profiles were compared. Plasma was also collected from mice that underwent sham operation (control mice, n=10). Plasma amino acid concentrations were measured by LC/MS/MS.
The plasma concentrations of several amino acids changed significantly in tumor-bearing mice compared to concentrations in control mice. Although cells from the same line were injected into the cecal wall of BALB/c mice and nude mice, a difference was noted in the change in plasma amino acid levels. Plasma Val, Ile, Leu, and Met levels decreased in BALB/c mice but increased in nude mice. There was no difference in the amino acid profile of CT26 tumor tissues between BALB/c mice and nude mice. We then injected antiCD3-antibody into the peritoneal cavity of tumor-bearing BALB/c mice (n=5) to eliminate T-cell function. We also injected IgG into tumor-bearing BALB/c mice (n=5) for control. The pattern of change in amino-acid profiles differed between the two groups of mice.
Our findings suggest that T-lymphocyte-mediated immunoreactions are involved in changes in the plasma amino acid profile in patients with colorectal cancer.
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-296. doi:10.1158/1538-7445.AM2011-LB-296
Abstract LB-302: Inhibition of STAT3 following systemic delivery of STAT3 antisense oligonucleotide results in target inhibition in tumor and tumor-associated stromal cells and dramatic reduction in circulating pro-tumorigenic cytokines
Authors: Kim Youngsoo , Hsu Jeff , Zhou Tianyuan , He Guobin , May Chris , Monia Brett P. , MacLeod Robert 
Published: August 2014

Abstract
Constitutive activation of STAT3 has been documented in a broad range of neoplastic tissues. STAT3 is a transcription factor that regulates the expression of numerous genes involved in the proliferation, survival, and metastasis of tumor cells. In addition, STAT3 contributes to tumorigenesis by modulating immune responses mediated by tumor stromal cells in the tumor microenvironment. The immuno-suppressive, pro-tumorigenic effects of STAT3 are regulated by induction or inhibition of several key cytokines. However STAT3 remains a difficult target to drug with conventional approaches. Here, we have studied the effects of selective downregulation of STAT3 in various cancer settings by optimized antisense oligonucleotides (ASOs). We assessed the effects of STAT3 downregulation on the expression of cytokines and the progression of cancer. Initially, the safety of inhibiting STAT3 was demonstrated in tolerability studies, where no notable toxicities were observed despite near complete abrogation of STAT3 expression in the liver following systemic delivery of ASO in both rodents and in non-human primate. ASO treatment led to STAT3 inhibition in tumor cells and several non-tumor stromal cell populations of the tumor. In addition, dramatic reduction in key pro-tumorigenic cytokines including IL-6 and IL-1b was observed in C26 colon cancer-bearing animals, which correlated with the decrease of STAT3 level in tumor and stromal cells. This result suggests that STAT3 might not only transmit the IL-6 signal from upstream pathway, but regulates IL-6 level possibly in an auto-feedback manner. Downregulation of STAT3 also led to the inhibition of IL-6-induced C-reactive protein (CRP) expression, which was recently reported to play a key role in the progression of multiple myeloma (MM). Moreover, inhibition of STAT3 resulted in a significant delay in tumor growth in STAT3-dependent MDA-MB-231 breast cancer and U251 glioblastoma xenograft models following systematic ASO treatment. The results from this study collectively suggest that STAT3 expression can be specifically modulated by ASOs in vivo tumor models and that in addition to effects in tumor cells STAT3 ASOs regulate the balance of tumorigenic cytokines in the tumor microenvironment.
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-302. doi:10.1158/1538-7445.AM2011-LB-302
Abstract LB-362: Both canonical and non-canonical autocrine Wnt signaling regulates clonogenic growth and epithelial-mesenchymal transition in colon cancer cells lacking mutational activation of Wnt pathway
Authors: Planutis Andryus , Planutiene Marina , Holcombe Randall F. , Planutis Kestutis 
Published: August 2014

Abstract
Introduction: Wnt signaling in cells with mutationally-induced constitutive pathway activation promotes clonogenic growth and epithelial-mesenchymal transition (EMT). The role of autocrine Wnt signals in colon cancer cells lacking a Wnt pathway activating mutation is less clear.
Hypothesis: Extracellular Wnt inhibitors will reduce clonogenic growth and EMT in colon cancer cell lines lacking mutational Wnt pathway activation by inhibiting basal levels of autocrine Wnt signaling. Methods: Two cells lines were utilized: HCT116B is a colon cancer cell line in which an abnormal beta-catenin allele has been removed by homologous recombination; RKO is a colon cancer cell line with no known Wnt pathway activation. The Wnt inhibitors DKK1, which blocks canonical Wnt signals by interaction with LRP5 and sFRP1 which blocks both canonical and non-canonical Wnt signals were utilized and transfected into each cell line. Canonical Wnt throughput was measured with a luciferase based reporter construct, clonogenic growth by colony formation in soft agar and EMT by morphology.
Results: Untransfected HCT116B, but not RKO expressed DKK1. Neither cell line expressed sFRP1. Both cell lines expressed significant quantities of DKK1 or sFRP1 after transfection. Canonical Wnt signaling was suppressed in RKO by both DKK1 and sFRP1 but only by DKK1 in HCT116B. DKK1 inhibited clonogenic growth in RKO but not in HCT116B, while sFRP1 inhibited it in both cell lines. EMT was clearly suppressed by these inhibitors in RKO; such an effect was less visible in HCT116B.
Discussion: Colon cancer cells lacking mutational activation of the Wnt pathway are susceptible to the actions of extracellular Wnt inhibitors, presumably via inhibition of autocrine Wnt signals and canonical Wnt signaling. However, cells with basal expression of a canonical Wnt inhibitor such as DKK1 (HCT116B) rely preferentially on non-canonical pathways for clonogenic growth and EMT which can be blocked by global Wnt ligand antagonists such as sFRP1. The importance of autocrine Wnt signaling and contributions by non-canonical pathways to clonogenic growth and EMT has important implications for the development of Wnt-targeted therapeutic agents for colon cancer.
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-362. doi:10.1158/1538-7445.AM2011-LB-362
Abstract LB-366: Patient-derived EBV-immortalized B-lymphocytes are a dominant contaminant of in vitro cultured human neuroblastoma tumor-initiating cells isolated from bone marrow
Authors: Påhlman Sven , Johnsson Sofie A. , Pietras Alexander , Wigerup Caroline , Øra Ingrid , Andäng Michael , Nilsson Kenneth , Olofsson Tor , Gisselsson David 
Published: August 2014

Abstract
Neuroblastoma is one of the most common solid tumors of infancy and is believed to originate from immature sympathetic nervous system progenitor cells. Tumor stem cells from different cancer forms have during the last decade been isolated and propagated in vitro in stem cell-promoting medium. These cells have given the opportunity to study the population within the tumor that is believed to be responsible for relapse and metastatic disease. Three years ago, putative neuroblastoma tumor-initiating cells (TICs) were isolated from bone marrow of patients with high stage disease. Several findings concerning these cells have been difficult to explain in a neuroblastoma context, i.e. that initially only cells from MYCN non-amplified tumors could be established as proliferating cultures in vitro, that they have a B-cell phenotype with VDJ rearrangement as presented at the 2010 Advances in Neuroblastoma Research (ANR) meeting, and as presented here, that they lack genomic imbalances and fail to recapitulate neuroblastoma morphology when xenografted. We show that these widely studied patient-derived TIC cultures (NB12, NB88 and NB122R), also at low passages, are highly contaminated by proliferating cells of a B-lymphocyte phenotype, with the absolute majority of cells expressing multiple B-cell antigens while lacking expression of neuroblastoma-associated markers. We further show that these lymphoblastoid cells are Epstein-Barr virus (EBV)-infected with robust expression of the two EBV nuclear antigens EBNA2 and EBNA3A. In addition, orthotopic and subcutaneous TIC-derived xenograft tumors all have EBNA2 and B-cell marker CD19 positive cells at a high frequency. Published and unpublished results based on the use of the proposed TIC lines as a model for neuroblastoma development should be considered with caution, as these lines, at least with time in culture, mainly consist of EBV-transformed B-lymphoblastoid cells.
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-366. doi:10.1158/1538-7445.AM2011-LB-366
Abstract LB-367: New evidence supports the potential use of methotrexate in children with MYCN-amplified neuroblastoma.
Authors: Lau Diana T. , Norris Murray D. , Marshall Glenn M. , Haber Michelle , Ashton Lesley J. 
Published: August 2014

Abstract
Background
Folate is essential for cell growth and differentiation. Cancer cells frequently up-regulate folate receptors to increase folate uptake to meet their elevated need for nucleotides to support DNA synthesis and growth. SLC19A1 encodes for a major folate or anti-folate transporter and has been reported to be regulated by oncogenic transcription factors. In childhood neuroblastoma, amplification of the MYCN oncogene is a strong prognostic marker for predicting unfavourable outcome. In light of previous findings showing that overexpression of SLC19A1 increases folate influx and methotrexate (MTX) sensitivity, we aimed to investigate the relationship between SLC19A1 expression, MYCN amplification and expression, to determine if this relationship modified MTX sensitivity in neuroblastoma.
Methods
Expression levels of SLC19A1 and MYCN were examined in 42 neuroblastoma patient samples and in two independent in vitro MYCN functional systems. The impact of MYCN amplification/expression and SLC19A1 expression on MTX sensitivity were evaluated on 13 neuroblastoma cell lines. SLC19A1 G80A polymorphism was also examined to determine its impact on SLC19A1 gene expression and MTX sensitivity.
Results
Expression levels of SLC19A1 and MYCN were positively correlated in neuroblastoma tumour samples (p=0.0001). Induction of MYCN in vitro increased the mRNA expression levels of SLC19A1 by 12-fold (p=0.0003) while silencing of MYCN reduced the expression levels of SLC19A1 by 7-fold (p=0.0017). Neuroblastoma cell lines with MYCN overexpression or amplification were at least 2000-fold more sensitive to MTX than those without (expression: p=0.0002; amplification: p&lt;0.0001). However, SLC19A1 G80A polymorphism did not appear to impact on SLC19A1 gene expression or MTX sensitivity.
Conclusions
Our data indicate a potential functional link between MYCN and the regulation of anti-folate uptake. Our findings suggest that MYCN amplification confers MTX sensitivity through the regulation of the folate receptor; SLC19A1. Targeting SLC19A1 mediated anti-folate uptake in patients with MYCN amplification may provide a new therapeutic approach in children with neuroblastoma.
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-367. doi:10.1158/1538-7445.AM2011-LB-367
Abstract LB-368: The reduction of Bmi-1 expression increases the sensitivity of prostate cancer the cell line PC3 to X-ray irradiation
Authors: Jason Gonzales C. , Fink Louis M. 
Published: August 2014

Abstract
Bmi-1 is a proto-oncogene that has been implicated in the polycomb complex that is required for cell proliferation and the maintenance of stem cells in a variety of tissues and cancers. Bmi-1 expression has been found to be elevated in a variety of tumors and its abundance has been correlated with survival. Previous studies have implicated Bmi-1 as having a role in radioresistance of cancer cells. In the present studies, we have shown that a stably integrated siRNA, which is conditionally regulated by doxycycline, can be used to study the susceptibility of prostate cancer cell line PC3 to radiation injury following a reduction of Bmi-1 expression.
Human HEK293 cells were transfected with lentiviral packaging plasmids and the pTRIPZ vector containing an RFP reporter gene upstream of the Bmi-1 siRNA. PC3 cells were stably transduced with the Bmi-1 siRNA via lentivirus and were initially selected for the puromycin resistance. The RFP reporter gene and Bmi-1 siRNA is under control of a tetracycline response element (TRE) and, following the administration of doxycycline, RFP and Bmi-1 siRNA are concomitantly expressed. Studies on the expression of RFP, Bmi-1 RNA expression by RT-PCR and Bmi-1 measurements by western blots confirm the stable conditional expression of Bmi-1 in prostate cancer PC3 cells.
The cell cycle analysis, the apoptotic rate and growth rates of the Bmi-1 expressing and non-expressing cell cultures were not significantly different. However, after treatment with 8 Gy x-irradiation, there was a marked increase in cells in the G2/M and in DNA fragmentation in the PC3 cells when Bmi-1 was reduced. There also was a marked decrease in the plating efficacy and in the cloning efficacy in methylcellulose.
Perhaps the delineation of the Bmi-1 status of the cells in a biopsy or in the circulating tumor cells of patients with PC can be used to predict the biological behavior and therapeutic response of these cancers. This study was supported by grant DE-FG02–08ER64608 from the DOE.
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-368. doi:10.1158/1538-7445.AM2011-LB-368