bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3403: Responsiveness to IGF-1R targeted therapy in osteosarcoma may be regulated by the 3179 G&gt;A mutation
Authors: Sowers Rebecca , Chung So-Hak , Zhang Wendong , Kolb E. Anders , Gorlick Richard 
Published: February 2011

Abstract
The insulin growth factor-1 receptor (IGF-1R) has been implicated in the pathogenesis of numerous pediatric malignancies, including osteosarcoma (OS), Ewing's sarcoma, and rhabdomyosarcoma. Historically, IGF-1R targeted therapies have been hindered by IGF-1R's structural similarity to the insulin receptor as well as toxicities associated with non-specific inhibition. A preliminary study of the effects of an IGF-1R monoclonal antibody in mouse osteosarcoma xenografts indicated that while some xenografts exhibited a complete response to the IGF-1R antibody, other xenograft samples exhibited no response. A possible explanation for the difference in response across the sample population is the presence of a genetic alteration in the IGF-1R gene.
Methods: Exons 1-20 of the IGF-1R gene were sequenced in four mouse OS xenograft samples (one “high response” sample, two “intermediate response” samples, and one “low response” sample) and in 87 OS primary tissue samples.
Results: The high response xenograft sample had a sequence alteration in exon 16 (3179 G&gt;A) that was not present in any of the low response or intermediate response xenograft samples. Of 87 OS primary tissue samples, 34 samples were homozygous wild type (GG), 33 samples were heterozygous (GA), and 20 samples were heterozygous mutant (AA). Additional sequence alterations were present in the OS primary tissue samples, but the 3179 G&gt;A mutation was the only alteration that differed between the responsive OS xenograft sample and the non-responsive OS xenograft sample.
Conclusions: The 3179 G&gt;A genetic alteration has been previously reported and does not represent a coding substitution; however, it may still play a role in OS tumor response, possibly through message stability or in conjunction with a series of related mutations. Due to genetic variability across cultured cell lines, in vitro functional assays will be performed on GG-expressing cell lines after the introduction of the AA mutation. Similarly, the GG mutation will be introduced to AA expressing cell lines to compare functional relevance of the 3179 G&gt;A alteration.
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 3403.
Abstract 3409: Arsenic trioxide inhibits Ewing sarcoma growth by blocking Hedgehog/GLI pathway
Authors: Beauchamp Elspeth M. , Rodriguez Olga , Albanese Christopher , Toretsky Jeffrey A. , Üren Aykut 
Published: February 2011

Abstract
Ewing's Sarcoma Family of Tumors (ESFT) is an undifferentiated neoplasm of the bone and soft tissue. ESFT is characterized by a specific chromosomal translocation occurring between chromosome 22 and (in most cases) chromosome 11, which generates an aberrant transcription factor, EWS-FLI1. We have previously shown that GLI1 is a direct transcriptional target of EWS-FLI1, and is important for ESFT tumorigenicity. Thus, GLI1 is a potential therapeutic target in ESFT. Arsenic Trioxide (ATO) is an FDA approved drug used for the treatment of Acute Promyelocytic Luekemia (APL) as a second line of therapy for those patients who don't response or relapse on All-trans-retinoic acid therapy. We show that Arsenic Trioxide inhibits GLI1 transcriptional activity. Arsenic Trioxide can also decrease the expression of GLI target genes without affecting GLI1 protein levels. We also show that ATO can inhibit the growth of ESFT cell lines in vitro and in vivo in a mouse xenograft model. To further prove that ATO is causing tumor cell growth inhibition by affecting GLI, we treated a mouse medulloblastoma model that is driven by an activating Smoothened mutation SMOA1. We were able to significantly improve survival of these mice with ATO treatment. Our results establish ATO as a hedgehog pathway inhibitor, and warrant the investigation of ATO in clinical trials as a new therapy for ESFT, basal cell carcinoma and medulloblastoma patients.
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 3409.
Abstract 3416: Cetuximab promotes immunotoxicity against rhabdomyosarcoma in vitro
Authors: Herrmann Delia , Seitz Guido , Warmann Steven W. , Bonin Michael , Fuchs Jörg , Armeanu-Ebinger Sorin 
Published: February 2011

Abstract
Novel treatment strategies have to be evaluated to improve the prognosis of advanced stage rhabdomyosarcoma (RMS) and to deal with clinical problems such as metastatic invasion, local tumor recurrence or multidrug resistance. Immunotherapy may represent an alternative specific, effective, less toxic and more promising therapeutic approach. Potential targets for antibody therapy of RMS are currently unknown. Differential gene expression analysis between the two main histopathological subtypes - embryonal and alveolar RMS - on 12 primary RMS samples was performed with Affymetrix array technology. Statistical analysis revealed 211 up-regulated and 323 down-regulated transcripts. Ingenuity Pathways analysis based on these results indicated the epidermal growth factor receptor (EGFR) as a central molecule with a 3.9-fold higher expression in embryonal compared to alveolar RMS. Subsequently, the expression of EGFR as well as the binding of the corresponding humanized antibody Cetuximab on embryonal (RD, A-204) and alveolar (Rh30) RMS cell lines was evaluated by flow cytometry. High expression of EGFR was detected in Rh30 and RD cells, whereas Cetuximab did not bind to A-204 at a concentration of 10 µg/ml. Next, the activity of Cetuximab was quantified using proliferation assays, in which viability of the above RMS cell lines ranged between 68% and 107% and was influenced neither by Cetuximab (concentrations ranging from 1 - 100 µg/ml) nor by 10 ng/ml EGF. However, antibody-dependent cellular cytotoxicity assays with PBMCs revealed potent activity of Cetuximab even at a low concentration of 0.05 µg/ml and a 3- to 4-fold enhanced specific lysis of RMS cells expressing EGFR. These promising effects of Cetuximab must now be tested in a suitable animal model.
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 3416.
Abstract 3417: Ezh2 is up-regulated and correlates with Ki67 and CD31 expression in human pediatric rhabdomyosarcoma
Authors: Ciarapica Roberta , Pezzullo Marco , Verginelli Federica , Boldrini Renata , Sio Luigi De , Stifani Stefano , Giordano Antonio , Rota Rossella 
Published: February 2011

Abstract
Rhabdomyosarcoma (RMS) is a pediatric tumor believed to originate from perturbations of the normal development of the muscle lineage. The Polycomb Group (PcG) protein Ezh2, which was originally implicated in inhibiting homeobox gene expression during embryonic development, was recently shown to act as a negative regulator of muscle differentiation. Moreover, Ezh2 is a histone methyltransferase that is aberrantly overexpressed in most human cancers. Comparing the level of the expression of Ezh2 in RMS cell lines, a small group of tumor samples with normal skeletal muscle myoblasts (SkMC), and normal muscle tissues, we have previously observed that Ezh2 is highly upregulated in rhabdomyosarcoma tumors (Ciarapica et al., 2009). The aim of this study was to characterize the relevance of Ezh2 expression in RMS. Ezh2 expression was analyzed by immunohistochemistry in a cohort of 32 RMS primary tumors and correlated with the expression of the cell proliferation marker, Ki67, and the angiogenic marker, CD31. Results of these expression studies were then correlated with the clinicopathological features of the tumor samples. No significant difference in the clinicopathological variables was observed between the two major histophatological groups of RMS, the most aggressive alveolar RMS (ARMS) and the embryonal RMS (ERMS). Ezh2 expression was not correlated with the clinical parameters of the cohorts, but strikingly, a significant positive correlation was observed between Ezh2 and Ki67 expression in the whole RMS sample (r0 = 0,560; p = 0,013). The number of the large vessels was correlated with the total number of vessels (r0= 0,730; p&lt;0,0001) and with the expression of Ki67 (r0= 0,421; p=0,02). In ARMS samples, the number of large vessels was significantly correlated with the expression of Ezh2 (r0= 0,559; p=0,047), the total number of vessels (r0= 0,781; p=0,02), and the expression of Ki67 (r0= 0,738; p=0,004). This study confirmed our previous observation regarding the aberrantly high expression of Ezh2 in rhabdomyosarcoma tumors on a larger cohort of samples. Moreover, the present data established a positive correlation between Ezh2 expression and the proliferative and angiogenic potential of rhabdomyosarcoma neoplasia.
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 3417.
Abstract 3418: Characterization of a survival pathway controlled by FGFR4 in alveolar Rhabdomyosarcoma
Authors: Wachtel Marco , Schäfer Beat 
Published: February 2011

Abstract
The inefficiency of the currently used conventional treatment modalities for alveolar Rhabdomyosarcoma (aRMS) stimulate the search for alternative treatment approaches such as targeted therapies exploiting addiction of tumors cells to specific signalling pathways. Indeed, inhibition of specific nodal points in such pathways such as growth factor receptors (e.g. IGF1R) was effective in preclinical model systems of aRMS and might advance to early clinical studies. However, experience from clinical studies of adult tumors suggests that tumor cells can escape such therapies targeting solely one signalling molecule via (re)activation of alternative pathways. Therefore, the evolution of tumor resistance needs to be addressed already in preclinical studies and might then be targeted upfront by employing an evidence-based combination approach.
Here, we describe a FGFR regulated survival pathway which is able to rescue aRMS cells from apoptosis induced by blocking other growth factor pathways. The relevant receptor is FGFR4, a direct target of the oncogenic PAX3/FKHR fusion protein, whose activation efficiently blocks apoptosis induced by an IGF1R inhibitor in different aRMS cell lines. On the other hand, combined inhibition of both FGFR4 and IGF1R pathways synergistically reduces aRMS cell viability, involving upregulation of Bcl-xl. Interestingly, the survival pathway downstream of FGFR4 does neither involve MEK/ERK nor Akt. Experiments defining the components of this pathway using genetic siRNA screens are currently underway.
Taken together, our data hint to a potential escape mechanism of tumor cells from therapies targeting the IGF1R/AKT axis via FGFR4 and suggests that combined inhibition of the FGFR4 and IGF1R pathways might be superior to single treatments.
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 3418.
Abstract 3425: Expression and functional role of erbB2 in human hepatoblastoma
Authors: Steiger Barbara , Leuschner Ivo , Denkhaus Dorota , von Schweinitz Dietrich , Pietsch Torsten 
Published: February 2011

Abstract
Background: The receptor tyrosine kinase erbB2 is known to play a role in the development of hepatic progenitor cells and is often found to be expressed and mutated in different solid tumors. Activated erbB2 is a marker of poor prognosis in several malignancies and to date, successful strategies have been developed to target erbb2 receptor. The aim of this study was to determine the expression of erbb2 in human hepatoblastoma, the most common primary hepatic malignancy in early childhood, and its functional role in hepatoblastoma cell biology.
Methods: Expression of erbB2 on the protein level was analyzed by Western Blot, immunofluorescence and RT-PCR of lysates of primary tumors and cell lines HuH6, HepT1, HepT3 and HepG2. Immunohistochemical staining was performed to determine phosphorylated erbB2 and subsequent kinases. Single strand conformation polymorphism (SSCP) analysis was used to scan known hotspots for mutations (exons 6, 8, 18-23 of erbB2) in a panel of 56 tumor samples. Cells were stimulated with rhHRG1-β. Activation of subsequent kinases was determined via Western Blot and MTT assay was used to determine proliferation after stimulation and overexpression of erbb2 via transient transfection. The influence of rhHRG1-β on the activity of the Wnt/ß-catenin pathway was measured by transfection with the TOP-/FOP-Flash reporter assay. The effects of erbB2 kinase knockdown by transient transfection with siRNA against erbB2 on apoptosis and proliferation were also evaluated.
Results: Expression of erbB2 was detected in all four cell lines and most of the primary tumors. Immunohistochemistry indicated expression of phosphorylated (activated) erbb2 proteins in 90% and activation of subsequent kinases, which are downstream targets of erbb2. Mutations were not present in the erbB2 gene. Stimulation with HRG1-β induced phosphorylation of Akt, Erk1/2 and p70S6K and resulted in increased cell proliferation. This effect was not mediated by an increase in activity of the Wnt/ß-catenin signaling pathway because TOP-Flash reporter activity was not further increased in the presence of rhHRG1-β. Overexpression of erbB2 resulted in enhanced proliferation after stimulation with HRG1-β in all four cell lines, whereas knockdown of erbB2 decreased the proliferative effect of HRG1-β on hepatoblastoma cell lines. Knockdown of erbB2 did not induce apoptosis in hepatoblastoma cell lines.
Conclusion: These results indicate that erbB2 might play an important functional role in hepatoblastoma cell biology. Further experiments are needed to evaluate the clinical significance.
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 3425.
Abstract 3426: The lower incidence of loss of IGF2 imprinting, but not that of WT1, WTX or CTNNB1 abnormality may cause different incidence rates of Wilms tumor between Japanese and Caucasian populations
Authors: Haruta Masayuki , Arai Yasuhito , Honda Shohei , Ohshima Junjiro , Kasai Fumio , Soejima Hidenobu , Okita Hajime , Hata Jun-ichi , Fukuzawa Masahiro , Kaneko Yasuhiko 
Published: February 2011

Abstract
Incidence rates of Wilms tumor (WT) markedly differ among ethnic groups; the epidemiological studies showed that the incidence of WT in Japanese children is about half of that of WT in Caucasian children. In Hawaii and Britain, the rates of WT in Asian descent were less than two-third or a half of those in Caucasian children, and these findings suggest that the different incidences of WT may be caused by genetic factor(s), but not by environmental factor(s). Development of WT is associated with mutations of certain genes, including WT1, WTX and CTNNB1, and abnormal expression of IGF2, namely, loss of imprinting (LOI). The frequency of these abnormalities occurs in 10-15% (WT1), 7-15% (WTX), 5-13% (CTNNB1) and 30-60% (IGF2 LOI) of sporadic WTs based on the studies in North-American or European children. To demonstrate the molecular characteristic in Japanese WT, we examined mutations/deletions of WT1, WTX and CTNNB1 using Southern blot, SNP array, sequencing and/or real-time PCR, and expression pattern of IGF2 using the ApaI polymorphism site in exon 9 and the methylation status of the CTCF binding site 6 at H19-differential methylated region (DMR) in 101 sporadic and 13 syndromic WTs in Japanese children. Abnormalities of WT1, WTX or CTNNB1 were detected in 24 (23.8%), 24 (23.8%), and 21 (20.8%)of 101 sporadic WTs, respectively, and in 13 (100%), 0, and 10 (76.9%) of 13 syndromic WTs, respectively. LOI of IGF2 was found in 24 (23.8%) of sporadic WTs and in 1 (7.7%) of syndromic WTs. Thus, the incidence of WT1, WTX or CTNNB1 abnormality was higher, but that of LOI of IGF2 was lower in Japanese children than in Caucasian counterparts. Because the incidence of WT in Japanese children is about half of that of WT in Caucasian ones, the population-based incidences of WT1, WTX or CTNNB1 abnormality may be similar between the two ethnic groups. In contrast, the incidence rate of IGF2-LOI in Japanese children was lower than those of IGF2-LOI in Caucasian children, and the difference in the population-based incidences is much larger. A recent study of 47 Japanese patients with Beckwith-Wiedemann syndrome revealed a significantly lower frequency of H19-DMR hypermethylation in Japanese patients than in North American and European patients (Sasaki et al, Eur J Hum Genet 2007). This and the present findings suggest that susceptibility to epigenetic alterations differs between Japanese and Caucasian populations.
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 3426.
Abstract 3441: Circulating perivascular progenitors, a target of PDGFRbeta inhibitors
Authors: Mancuso Patrizia , Calleri Angelica , Marighetti Paola , Quarna Jessica , Curigliano Giuseppe , Martin-Padura Ines , Bertolini Francesco 
Published: February 2011

Abstract
Cancer blood vessels consist of two interacting types of cells: inner lining endothelial cells and surrounding perivascular cells (pericytes, vascular smooth muscle cells or mural cells). Marrow-derived PDGFRbeta(CD140b)+ progenitor perivascular cells (PPC) can differentiate into pericytes and regulate vessel stability and vascular survival in tumours (Song et al, Nature Cell Biol 2005). Similarly to what we have done with circulating endothelial cells and progenitors (Mancuso et al, Clin Cancer Res 2009), we have developed and validated a flow cytometry procedure for the enumeration of circulating PPC and the study of their viability in murine models of cancer and in cancer patients. DNA+CD45-CD31-CD140b+ cells were enumerated by six-colour flow cytometry, their perivascular nature was confirmed by electron microscopy and RT-PCR expression of CD140b, and their viability was assessed by 7AAD. PPC were found to circulate in cancer-bearing mice, and to be increased (compared to age-matched healthy controls) in patients affected by some types of cancer such as metastatic breast and kidney cancer. In murine models of cancer and in cancer patients, at variance with the kinetcs of circulating endothelial progenitors (Bertolini et al, Cancer Res 2003; Shaked et al, Cancer Cell 2008), cyclophosphamide-based chemotherapy reduced the number of viable PPC, most likely because of an increase of PPC recruitment towards vessels damaged by cyclophosphamide administration (Bertolini et al, Lancet Oncology 2001). Conversely, the administration of the tyrosine kinase inhibitor (TKI) sunitinib, known to inhibit PDGFRbeta, was associated in murine models and human cancer patients with an increase of apoptotic circulating PPC, suggesting a direct targeting of these cells. Studies are ongoing to validate PPC enumeration and viability assessment as a surrogate marker of clinical efficacy in preclinical models and in cancer patients receiving multiple TKI inhibitors including an anti-PDGFRbeta activity.
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 3441.
Abstract 3448: Synergistic effect of benzo(a)pyrene (BaP) and dietary fat on biotransformation enzymes, DNA adducts and colon tumors in ApcMin mice
Authors: Harris Deacqunita L. , Washington Mary K. , Hood Darryl B. , Roberts Lyman J. , Ramesh Aramandla 
Published: February 2011

Abstract
Studies in our laboratory thus far have shown formation of colon tumors in ApcMin mice subsequent to ingestion of fat containing BaP, an environmental carcinogen. These findings have human health relevance in that around 60,000 lives/year are lost to colon cancer in US alone. Diet and environment have been implicated in the development of sporadic colon tumors. Since biotransformation of toxicants is one of the factors that trigger carcinogenesis, the objective of this study was to determine how dietary fat potentiates the development of colon tumors through altered BaP biotransformation, using the ApcMin mouse model. Benzo(a)pyrene was administered to ApcMin mice in unsaturated- (peanut oil) and saturated- (coconut oil) fats at doses of 50 and 100 μg/kg via oral gavage over a 60-day period. Blood, colon and liver were collected at the end of exposure period. The expression of BaP biotransformation enzymes (CYP1A1, CYP1B1 and GST) in liver and colon were assayed at the level of mRNA and activities. Tissue samples were analyzed by reverse phase-HPLC for BaP metabolites, and 32P-postlabeling method for BaP- DNA adducts. BaP exposure through dietary fat altered its biotransformation in a dose-dependent manner, with 100 μg/kg dose group registering an elevated expression of BaP biotransformation enzymes, greater concentration of BaP metabolites, BaP-DNA adducts and more adenomas compared to the 50 μg/kg dose group (p &lt; 0.05). This effect was more pronounced for saturated fat group compared to unsaturated fat group (p &lt; 0.05). These findings establish that saturated fat contributes to sustained induction of BaP biotransformation enzymes and extensive metabolism of this carcinogen. As a consequence, the reactive metabolites such as epoxides and quinones generated in colon bind with DNA, and form adducts resulting in colon tumors in a long term exposure situation (funded by NIH grants S11ES014156, 1F31ES017391-01, 5T32 HL007735-14 and RO3CA130112-01).
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 3448.