bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5344: Genome-wide identification of PAX3-FKHR binding sites in rhabdomyosarcoma reveals candidate target genes important for development and cancer
Authors: Cao Liang , Yu Yunkai , Bilke Sven , Walker Robert L. , Azorsa David O. , Helman Lee J. , Meltzer Paul S. 
Published: June 2012

Abstract
The paired box transcription factor (PAX) family consists of 9 highly related members with critical roles in organogenesis and tissue specification during development, including skeletal muscle, pancreas, central nervous system, kidney, and immune system. In various cell model systems, PAX genes have been implicated in the maintenance of the multipotent state, the initiation of differentiation programs, cell migration, proliferation and survival. Mutations and gene rearrangement of PAX genes are frequently associated with human diseases and cancers. In particular, PAX3 and PAX7 are required during early embryogenesis for the development of the neural-crest and skeletal muscle, and gene rearrangements with FKHR are frequently implicated with rhabdomyosarcoma (RMS). The PAX3-FKHR fusion protein is present in the majority of alveolar rhabdomyosarcoma (ARMS) associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first and unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in ARMS, with a novel monoclonal antibody specific for the fusion protein. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are: 1) mostly distal to transcription start sites; 2) conserved; 3) enriched for PAX3 motifs; and 4) strongly associated with genes over-expressed in PAX3-FKHR positive RMS cells and tumors. There is little evidence in our dataset for PAX3-FKHR binding at the promoters. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common co-regulation for many target genes. We further provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The study is the first genome-wide analysis of direct targets for a PAX protein. The map of PAX3-FKHR binding sites provides the frame work for the understanding of PAX3-FKHR pathogenic roles and molecular targets to allow a systematic evaluation of agents against this aggressive RMS.
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 5344. doi:10.1158/1538-7445.AM2011-5344
Abstract 5345: A novel small molecule, XZH-5 inhibits constitutive and interleukin-6-induced STAT3 phosphorylation in human rhabdomyosarcoma cells
Authors: Liu Aiguo , Liu Yan , Xu Zhenghu , Yu Wenying , Wang Hong , Li Chenglong , Lin Jiayuh 
Published: June 2012

Abstract
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite the fact the improved treatment for Rhabdomyosarcoma has resulted in a remarkable increase of overall survival, the children with metastatic Rhabdomyosarcoma still have only a 3-year failure-free survival rate of less than 30%. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in most types of cancer including human RMS. STAT3 is considered to be an oncogene due to its ability to promote malignancy in mice. Given the oncogenic functions of STAT3 and the promise of inhibiting it, directly targeting STAT3 signaling represents a potential therapeutic approach to treating Rhabdomyosarcoma. Using structure-based drug design, we developed a novel small molecule, named XZH-5. In this study, we characterized the inhibitory effects of XZH-5 on STAT3 phosphorylation in four Rhabdomyosarcoma cell lines. XZH-5 competes with/inhibits the STAT3-SH2 dimerization through phosphorylated Tyr705 in all four Rhabdomyosarcoma cell lines. We also demonstrated a similar inhibition of STAT3 phosphorylation and induction of apoptosis by a previously known small molecular STAT3 inhibitor Stattic in Rhabdomyosarcoma cells. These results supporting Rhabdomyosarcoma cell lines are sensitive to STAT3 inhibition. In addition, XZH-5 inhibited STAT3 DNA binding activity and the expression of STAT3 downstream genes including Bcl-2, Bcl-xl, Cyclin D1 and Survivin. The inhibition of STAT3 in Rhabdomyosarcoma cells resulted in the induction of apoptosis, reduction of colony forming ability, and inhibition of cell migration. Furthermore, XZH-5 inhibited IL-6-induced STAT3 phosphorylation and STAT3 nuclear translocation. In contrast, it had no effect on IFN-γ-induced STAT1 phosphorylation, indicating the more selective effects on STAT3. These results demonstrated that Rhabdomyosarcoma cells are sensitive to STAT3 inhibition and STAT3 is a therapeutic target. Our results also suggested that XZH-5 may serve as a potential therapeutic agent for targeting STAT3 for Rhabdomyosarcoma treatments.
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 5345. doi:10.1158/1538-7445.AM2011-5345
Abstract 5354: Characterisation of the cell line HC-AFW1 derived from a paediatric hepatocellular carcinoma
Authors: Armeanu-Ebinger Sorin , Wenz Julia , Seitz Guido , Leuschner Ivo , Handgretinger Rupert , Fuchs Jörg , Warmann Steven W. 
Published: June 2012

Abstract
Paediatric hepatocellular carcinoma (HCC) has an incidence of 1.5 cases per million children and is linked to viral hepatitis in endemic regions. In Europe childhood HCC mostly arises in otherwise healthy liver and has an unknown ethiology. Current treatment results of HCC are dissatisfactory due to advanced disease at diagnosis and lacking response to chemotherapy. To improve the research of childhood HCC and to address specific therapeutic approaches a preclinical model for childhood HCC is needed. So far, there has been one existing cell line, HepG2, which has lately been discussed controversially as being hepatoblastoma. We established a cell line HC-AFW1 from the tumor of a 5 year old boy. The original tumor histology was characteristic as transitional liver cell tumor including hepatoblastoma and HCC morphology. These histological findings were confirmed through several reference pathology laboratories worldwide. The cell line HC-AFW1 was established by xenotransplantation of original tumor into immuno-deficient mice and re-culturing in vitro. The cell line is in sable culture now for over 8 months with a doubling time of 40 h. Cultured cells present epithelial characteristics and express hepatoma proteins like AFP, glypican 3, E-cadherin, CD10, CD326, HepPar1, Vimentin and Desmin. Catenin beta shows a deletion of 49 amino acids in the exon 3 involving the phosphorylation sites of GSK3 and was detected in cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. This involves chromosomal aberrations found in hepatoblastoma as well as in adult HCC. Several alterations of gene copy numbers were detected by genome wide SNP array. Among different tested drugs cisplatin and irinotecan showed an effective inhibition of tumor cell growth in an MTT assay at concentration below 5 µg/ml. Transplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growing dedifferentiated tumors with high levels of serum AFP. This xenotransplants as well as stable cultured cells solely consist of HCC components suggesting a selection of HCC and degeneration of formally hepatoblastoma tumor parts. Therefore, HC-AFW1 is the first paediatric HCC-derived cell line and represents a valuable tool to investigate the biology and therapeutic strategies in childhood 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 5354. doi:10.1158/1538-7445.AM2011-5354
Abstract 536: A hypoxia-activated protein switch as a potential anticancer therapeutic
Authors: Wright Chapman M. , Ostermeier Marc , Eshleman James R. 
Published: June 2012

Abstract
We have engineered yeast cytosine deaminase (CD) to be activated by the tumor marker, hypoxia-inducible factor 1-alpha (HIF-1a) – turning on its ability to convert 5-fluorcytosine (5FC) into the chemotheraeutic drug 5-fluoruracil (5FU). HIF-1a is overexpressed in many types of cancer but is virtually undetectable in normal tissue due to rapid degradation. We sought a “tumor-sensing” protein whose prodrug converting activity is activated in the presence of HIF-1a. Such a protein would have advantages over therapeutic treatments such as gene-directed enzyme prodrug therapy (GDEPT). Our approach would circumvent the need for specific delivery of the “suicide” gene, which is a requirement in GDEPT, since the selectivity occurs at the protein level and not the gene delivery level. To create our desired protein, we constructed a library of fusion proteins between CD and the CH1 domain of p300 – a domain known to interact with HIF-1a. This library was subjected to a two-tiered genetic selection in E. coli designed to identify genes that conferred increased sensitivity to 5FC when HIF-1a was co-expressed. We identified a library member (HIF-1a activated protein switch 59, “Haps59”), which conferred to E. coli sensitivity to 5FC equivalent to wildtype CD but only in the presence of co-expressed HIF-1a. In the absence of HIF-1a, Haps59 did not confer any sensitivity to 5FC. We created a stable cell line of RKO expressing Haps59 to determine its ability to sensitize them to 5FC. RKO is a colorectal cancer cell line known to accumulate high levels of HIF-1a in hypoxic conditions. RKO cells stably expressing Haps59 in hypoxia were 10-fold more sensitive to 5FC than the same cells in normoxia. This sensitivity was shown to be a result of the presence of 5FC, Haps59, and HIF-1a in RKO cells, and the removal of either of these components resulted in normal cell growth. Further, we demonstrated the direct intracellular interaction of HIF-1a and Haps59. RKO cells expressing Haps59 were used to create xenografts in mouse models. Initial results from experiments using systemically administered 5FC to treat these xenografts will be presented.
Using advanced protein engineering techniques, we have created a protein that confers sensitivity to 5FC in the presence of the tumor-marker, HIF-1a. We believe that the Haps59 gene could have therapeutic potential for the treatment of solid tumors that exhibit elevated HIF-1a levels. Our strategy circumvents a limitation of GDEPT by not requiring selective delivery of the gene to cancer 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 536. doi:10.1158/1538-7445.AM2011-536
Abstract 5364: AURA kinases as markers and targets in GIST
Authors: Yen Chueh-Chuan , Chun-Nan Yeh , Hwang Tsann-Long , Chen Miin-Fu , Tzeng Cheng-Hwai , Chao Ta-Chung , Fletcher Jonathan A. 
Published: June 2012

Abstract
Mitotic index has been found to be an important prognostic factor in primary gastrointestinal stromal tumor (GIST). By using gene sets related to cell cycle (Proc Natl Acad Sci U S A. 2008; 22;105(3):955-60), we can stratify a group of patients with advanced GIST (J Clin Oncol 2008;26:4100-4108.) into two risk groups with distinct survival. So it is interesting to explore whether genes involved in regulation of cell cycle could be used as a target in treating GIST. Aurora kinase A (AURKA) and B (AURKB) were two important genes in cell cycle regulation. In the same cohort of patients, expression levels of both AURKA and AURKB were found higher in high risk group patients than those in low risk group. By using MTT assay, GIST882, an imatinib-sensitive GIST cell line, was relatively resistant to both AURKA inhibitor MLN8237 and AURKB inhibitor ZM447439 than GIST 48IM, an imatinib-resistant GIST cell line. MLN8237 could induce significant cell cycle arrest in both GIST cell lines, but apoptosis could only be seen in GIST48IM. On the other hand, after ZM447439 treatment, cell cycle inhibition could only be found in GIST48IM, and none of them had apoptosis. Instead, ZM447439 could induce autophagy in both cell lines. We then used immunohistochemistry (IHC) to examine 76 primary GIST patients. High expression of AURKA but not AURKB was more often seen in non-gastric GIST. In univariate analysis, patients with tumors having strong AURKA IHC staining, as well as large tumor size, high mitotic index and NIH high risk group, had significant lower survival than comparative groups. However, in the multivariate analysis, only high mitotic count and high AURKA expression were independent adverse prognostic factors. In conclusion, cell cycle-related genes could be used in predicting prognosis in advanced GIST, and cell cycle regulated genes such as AURKA and AURKB could be used as treatment targets.
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 5364. doi:10.1158/1538-7445.AM2011-5364
Abstract 537: Mechanisms by which pantoprazole, a proton pump inhibitor, enhances the activity of doxorubicin in solid tumors
Authors: Tan Qian , Patel Krupa , Lee Carol M. , Zhang Junyan , Joshua Anthony , Koritzinsky Marianne , Wouters Bradly G. , Tannock Ian F. 
Published: June 2012

Abstract
Purpose: Mechanisms of tumour resistance to cytotoxic drugs in solid tumours include limited drug distribution from tumour blood vessels and other effects of the tumour microenvironment. Proton pump inhibitors, such as pantoprazole (PTP), raise endosomal pH and thereby decrease sequestration of basic drugs in acidic compartments. This may allow more drugs to interact with DNA, while decreased net cellular uptake of drug, may allow more drugs to penetrate tissue to distal cells. PTP might also inhibit autophagy, a possible target for anticancer therapy, since endosomes are important intermediaries of this process. Here we describe the effects of PTP on doxorubicin uptake and distribution in cell cultures and solid tumours, and effects to cause growth delay. We have also evaluated the effect of PTP on autophagy of tumour cells.
Methods: Endosomal pH of cells was measured by using Lysosensor and fluorescence spectroscopy. Cytotoxicity was evaluated by a colony-forming assay. Doxorubicin distribution was quantified in MCF-7 xenografts by immunohistochemistry, in relation to blood vessels (recognized by an antibody to CD31), and regions of hypoxia (recognized by an antibody to EF5), with and without pre-treatment with PTP. Anti-tumour effects were evaluated by growth delay following treatment with single or multiple doses of doxorubicin with and without PTP. Effects of PTP on autophagy were evaluated by (i) expression of the LC3II protein by Western blotting and (ii) effects of PTP on prostate cancer PC3 cells transfected with green fluorescent protein) and with LC3 protein (a marker of autophagy) tagged with red fluorescent protein (mRFP-GFP-LC3 cells)
Results: PTP increased endosomal pH and decreased endosomal sequestration of doxorubicin in cultured cells. Pre-treatment with PTP increased the distribution of doxorubicin in solid tumours. PTP alone had no effect on tumour growth but increased the effect of doxorubicin to cause growth delay of human tumour xenografts with no apparent increase in toxicity. PTP showed marked effects to inhibit autophagy in cultured tumour cells in a dose and time dependent manner.
Conclusions/Discussion: PTP increases the effectiveness of doxorubicin against solid tumours and this combination is being investigated in a phase I clinical trial. Potential mechanisms underlying this effect include inhibition of sequestration of doxorubicin in endosomes permitting better drug distribution, and inhibition of autophagy.
Supported by a research grant from the Canadian Institutes of Health Research
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 537. doi:10.1158/1538-7445.AM2011-537
Abstract 5383: Inhibition of MCL-1 in mammary and CNS tumor cells promotes cell death in vitro and in vivo
Authors: Hamed Hossein A. , Mitchell Clint , Dent Paul , Yacoub Adly , Tye Gary , Bareford Mary Danielle 
Published: June 2012

Abstract
Treatment of cells with the BH3 domain/MCL-1 inhibitor obatoclax enhanced the lethality of lapatinib in a synergistic fashion in multiple tumor cell types, including ER+; HER2+; triple negative breast cancer cells and glioblastoma and medulloblastoma cells. Knock out of MCL-1 and BCL-XL enhanced lapatinib toxicity to a similar extent as obatoclax and suppressed the ability of obatoclax to promote lapatinib lethality. Pre-treatment of cells with lapatinib or with obatoclax enhanced basal levels of BAX and BAK activity and further enhanced drug combination toxicity. In vitro, treatment of breast cancer cells with obatoclax and lapatinib enhanced the toxicity of ionizing radiation. In vivo tumor growth data in xenograft and syngeneic model systems of breast cancer confirmed our in vitro findings. Lapatinib and obatoclax interacted to suppress mammary tumor growth in vivo without causing toxicity to multiple normal tissues including brain, heart, lungs, liver or kidneys.
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 5383. doi:10.1158/1538-7445.AM2011-5383
Abstract 5386: Therapeutic efficacy of RMLV vectors in human and murine glioma models
Authors: Inagaki Akihito , Hiraoka Kei , Logg Christopher R. , Kamijima Shuichi , Ostertag Derek , Perez Omar D. , Gruber Harry E. , Jolly Douglas J. , Robbins Joan M. , Kasahara Noriyuki 
Published: June 2012

Abstract
Unique among replicating viruses being developed as oncolytic agents, replicating murine leukemia virus (RMLV) retroviruses propagate without immediate lysis of host cells and maintain viral persistence through stable integration. Due to its intrinsic inability to infect quiescent post-mitotic cells and susceptibility to innate antiviral defenses that exist in normal cells but are inactivated in many cancers, RMLV vector replication has been shown to be highly tumor-selective. We have previously demonstrated that RMLV vectors are capable of highly efficient replication in tumor cells, and we have found significantly enhanced survival benefit in a variety of cancer models in vivo when RMLV vectors are employed for delivery of prodrug activator genes such as yeast cytosine deaminase (yCD), which mediates the conversion of inactive prodrug 5-fluorocytosine (5FC) to the anti-cancer drug, 5-fluorouracil (5FU). In the present study, we tested a newly developed RMLV vector with modified virus backbone sequences and a codon-optimized yCD gene (Toca511). First, we examined in vitro cytotoxicity using human (U87) and murine (TU-2449) glioma cell lines by MTS assay. The cell viability of Toca511-transduced cells was reduced by &gt;80% after 5 or 8 days of exposure to the prodrug, respectively. Second, we examined the therapeutic efficiency of this newly developed vector in subcutaneous U87 human glioblastoma models and TU2449 syngeneic mouse models. Toca511-mediated prodrug activator therapy strongly inhibited tumor growth in both subcutaneous models. Third, therapeutic efficacy was evaluated, and the minimum effective doses of 5FC prodrug and Toca511 vector determined in an intracranial U87 xenograft model. Systemic administration of 5FC resulted in significant inhibition of bioluminescent signals in mice whose tumors had been infected with Toca511 but not in control mice, associated with significant survival benefit even after injecting only 1×1e3 total vector units (p=0.0015). These data suggest that we have been successful in developing an improved retrovirus vector that shows strong therapeutic efficacy when used for prodrug activator gene therapy in both subcutaneous and intracranial xenograft models of human and/or murine glioma. This vector has now entered Phase I/II clinical trials for glioblastoma. Now, with the use of RMLV vectors such as Toca511, the original promise of retrovirus-mediated gene therapy strategies for cancer may finally be fulfilled.
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 5386. doi:10.1158/1538-7445.AM2011-5386
Abstract 5387: Prostate-targeted radiosensitization via aptamer-shRNA chimeras
Authors: Ni Xiaohua , Zhang Yonggang , Ribas Judit , Chodhury Wasim H. , Castanares Mark , Zhang Zhewei , Laiho Marikki , DeWeese Theodore L. , Lupold Shawn E. 
Published: June 2012

Abstract
Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to non-cancerous tissues. Radiation-sensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery these agents will also sensitize surrounding normal tissues. Here we describe the development and application of prostate-targeted RNA interference agents which selectively sensitize PSMA-positive cells to IR. A high throughput siRNA screen identified DNA-PK, MAD2L2, BRCA2, NBN, RAD23B, and RAD54L as candidate DNA-repair pathway targets for prostate cancer radio-sensitization. When candidate shRNAs were conjugated to the PSMA-targeting RNA aptamer, A10-3, they were selectively delivered into PSMA positive prostate cancer cells in the absence of traditional transfection reagents. The shRNA portion was then processed by dicer to the corresponding siRNA. DNA-PK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNA-PK in PCa cells, xenografts and human prostate tissues. The mechanism of DNA-PK knock-down was confirmed to be through RNA interference by 5’-RACE assay. In tumor injection models A10-3-DNA-PK-shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. This treatment extended time to reach quadruple tumor volume by approximately 10 weeks when compared to only one week in tumors treated with radiation and control aptamer-shRNAs. A10-3-DNA-PK-shRNA and radiation had no affect on the PSMA negative PC-3 tumors. These studies support aptamer-shRNAs as selective sensitizing agents which may improve the treatment of high-risk localized PCa.
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 5387. doi:10.1158/1538-7445.AM2011-5387