bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5578: IGF-1R nuclear staining in tumor cells identifies sarcoma patients with a prolonged progression free survival after IGF-1R monoclonal antibody therapy
Authors: Asmane Irene , Watkin Emmanuel , Marec-Berard Perrine , Ray-Coquard Isabelle , Alberti Laurent , Cassier Philippe , Decouvelaere Anne-Valerie , Ranchere Dominique , Kurtz Jean-Emmanuel , Bergerat Jean-Pierre , Blay Jean-Yves 
Published: August 2012

Abstract
Rationale A small proportion of patients with sarcoma achieves prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab). A biomarker identifying in routine those patients beforehand would be useful to select patients. The aim of this study is to identify predictive factors for PFS in soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma patients receiving IGF-1R Ab. Methods The series of patients with unresecable or metastatic STS, ES, or osteosarcomas treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Leon Berard was studied. Tumor samples were analyzed by immunohistochemistry for expression of IGF-1R, IGFBP-3, Ki-67, HER1 and HER2. Results All tumor samples had a positive IGF-1R immunostaining on 60% to 100% of cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=3, 19%), or nuclear + cytoplasmic (n=4, 25%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS or overall survival (OS). HER2 and HER1 stainings were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunostaining for IGF-1R was significantly associated with an increased PFS (p=0.009) and OS (p=0.04). Conclusion Exclusive nuclear localization of IGF-1R in sarcomas using routine immunohistochemistry was correlated to PFS and OS after IGF1R Ab treatment in this single center series. This observation is consistent with recent data reporting that nuclear localization of IGF-1R in tumor cells is a hallmark of pathway activation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5578. doi:1538-7445.AM2012-5578
Abstract 5579: Genomic approach to the prediction of chemotherapeutic sensitivity in osteosarcoma
Authors: Iwata Shintaro , Ohira Miki , Kamijo Takehiko , Yonemoto Tsukasa , Ishii Takeshi , Tatezaki Shin-ichiro , Nakagawara Akira 
Published: August 2012

Abstract
PURPOSE: Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. Despite of recent progress of combined therapy, about 30% of OS patients die because of tumor progression or relapse. It is generally accepted that sensitivity of neoadjuvant chemotherapy is the most important prognostic factor for OS, however, there have been few analyses documenting molecular markers that predicts the chemosensitivity of OS patients. The aim of this study is to identify possible genomic biomarkers for the prediction of chemosensitivity and prognosis for OS patients. METHODS: Pretherapeutic biopsy samples of 22 pediatric OS patients treated in Chiba cancer center who had homogeneous clinicopathological- and therapeutic- background were analyzed. In our study, patients were divided into 3 groups; group A includes 8 patients who demonstrated a good response for 1st regimen, group B includes 6 patients who were resistant to 1st regimen but showed good response to 2nd regimen, group C includes 8 patients who did not respond to neither 1st nor 2nd regimen. Genomic DNAs were prepared from each frozen tissue and used for aCGH analysis with Agilent 44k DNA microarray. RESULTS: According to the results of comparative analysis of CNV patterns in each patient, three chromosomal patterns strongly separated group A from B&C or C from A&B were identified. Gain of 5p12 was found in 7 out of 8 patients of group A, while only 1 out of 14 patients of group B and C (sensitivity 87.5%, specificity 92.9%). On the other hand, loss of 9q21 and amplification of 12q14 were specifically observed in group C, but not in A and B (sensitivity 100%, specificity 92.9%). The average of copy numbers within the region of 5p12 and 9q21.3 on each patient were calculated, and 2-dimensional plot of these two values clearly showed that each group formed distinct clusters. CONCLUSION: Our results indicated that copy number changes in OS biopsy samples could be good markers to determine suitable chemotherapeutic regimen for individual patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5579. doi:1538-7445.AM2012-5579
Abstract 5597: Modulating therapeutic effects of c-Src inhibitor via estrogen receptor and HER2 in breast cancer cell lines
Authors: Fan Ping , McDaniel Russell E. , Kim Helen R. , Jordan V Craig 
Published: August 2012

Abstract
Estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are two successful therapeutic targets in breast cancer. c-Src functions as an important adapter protein with ER and HER2, which validates it as an attractive target for the treatment of breast cancer. However, a very recent phase II clinical trial shows that a c-Src inhibitor, dasatinib, had limited single-agent activity in patients with HER2+ and/or hormone receptor (HR)+ advanced breast cancer (Mayer E et al. Clin Cancer Res 2011, Epub ahead of print). Therefore, a specific c-Src inhibitor, PP2, was utilized to block c-Src activity to identify targeted vulnerabilities affected by ER and HER2 in a panel of breast cancer cell lines (i.e. MCF-7, T47D, ZR-75-1, BT474, MCF-7:5C, MCF-7:2A, MDA-MB-231, Sk-Br-3, MCF-7/F, and T47D:C42). The antiproliferative effect of PP2 correlated with blocking c-Src mediated ERK/MAPK and/or PI3K/Akt growth pathways. The signaling pathways of c-Src were modulated by ER and HER2 in breast cancer cells. Inhibition of c-Src tyrosine kinase predominantly blocked ER negative breast cancer cell growth, particularly the triple (i.e. ER, PR, and HER2) negative cells. In contrast, ER negative Sk-Br-3 cells with highest HER2 phosphorylation were resistant to PP2, in which over-activated HER2 directly regulated growth pathways but not through c-Src. However, blocking c-Src recovered ER expression which made Sk-Br-3 cells regain responses to 4-hydroxytamoxifen. The majority of ER positive breast cancer cells were not sensitive to PP2 regardless of wild-type or endocrine resistant cell lines. Overall, c-Src mediates the essential role of growth pathways in ER negative breast cancer cells without HER2 over-activation. ER expression and HER2 over-activation are two important predictive biomarkers for the resistance to a c-Src inhibitor. These data provided an important therapeutic rationale for patient selection in clinical trials with c-Src inhibitors in triple negative breast cancer. Acknowledgements This work (VCJ) is supported by the SU2C (AACR) Grant (SU2C-AACR-DT0409).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5597. doi:1538-7445.AM2012-5597
Abstract 560: Development of an organotypic raft culture system to study the role of latent membrane protein 1 during Epstein-Barr virus replication
Authors: Geiser Vicki M. , Girard Julie , Godsil Mathias , Kahler Thomas , Rausch Emily , Rutledge Hayley 
Published: August 2012

Abstract
Epstein-Barr Virus (EBV) is a gamma herpesvirus that is prevalent worldwide and is an important cause of acute and chronic disease. Primary EBV infection which occurs after early childhood often results in acute infectious mononucleosis. Persistent latent EBV infection is a causative agent of anaplastic nasopharyngeal carcinoma, AIDS related lymphoma, posttransplant lymphoma, and Hodgkin's disease. Expression of Latent Membrane Protein 1 (LMP1) is common to most EBV related malignancies. LMP1 induced NF-κB activity is required for efficient transformation and survival of primary human B lymphocytes into lymphoblastoid cell lines. Increasing evidence suggest that LMP1 has an important role in the lytic cycle. Studies indicate that LMP1 and other latent genes are induced as part of the EBV lytic cascade in Burkitt's lymphomas. Our recent research indicates that LMP1-deleted virus replicates as efficiently as wildtype virus in HEK293 cells which suggests that the role of LMP1 during lytic replication is linked to changes in the cellular environment. LMP1 expression is associated with survival signals and alters expression of several differentiation markers, therefore a role for LMP1 during lytic replication in differentiating epithelial cells should be pursued. We have developed an organotypic raft culture system that will permit investigation of EBV replication in differentiating epithelial cells. Our lab is utilizing molecular, biochemical, and genetic approaches to elucidate the role of LMP1 during EBV replication in differentiating epithelial cells. We are investigating the function of LMP1 in viral replication, cell proliferation and differentiation, and viral-cellular signaling pathways. Based on these studies we will develop a model for the role of LMP1 during EBV replication in differentiating epithelial cells and its resulting pathogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 560. doi:1538-7445.AM2012-560
Abstract 5610: Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells
Authors: Tsai Wen-Bin 
Published: August 2012

Abstract
Arginine (Arg) depletion with pegylated recombinant arginine deiminase (ADI-PEG20), a novel strategy under clinical investigations for treating Arg-auxotrophic malignancies in humans, has produced promising results in several types of cancer, including malignant melanoma. These tumors are sensitive to ADI-PEG20 because they do not express argininosuccinate synthetase (AS), the rate-limiting enzyme for the de novo biosynthesis of Arg, and therefore require Arg from extracellular source for survival. ADI-PEG20 treatment, which catalyzes the conversion of Arg into citrulline and ammonia, results in Arg deprivation. Melanoma cells develop ADI-resistance because of induced AS upregulation. We previously demonstrated that induction of AS expression by ADI-PEG20 involves upregulation of transcription regulator c-Myc that positively regulates AS expression, but the underlying mechanism of c-Myc induction is not known. Here, we show that ADI-PEG20 activates Ras signaling and its downstream ERK and PI3K/Akt/GSK-3β kinase cascades. These cascades phosphorylate c-Myc, resulting in c-Myc stabilization by attenuating the ubiquitin-mediated protein degradation mechanism. Furthermore, we demonstrated that intervention of these signaling pathway using PI3K/Akt inhibitors suppressed c-Myc induction and enhance ADI-mediated cell killing. Because the Ras activation signaling is known to play important roles in tumor growth, our findings have important implications in Arg-deprivation and cancer cell metabolism and suggest that targeting the Ras signaling pathway may be beneficial in ADI-PEG20 anti-cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5610. doi:1538-7445.AM2012-5610
Abstract 5611: A synthetic lethality combination with chloroquine and rapamycin on chemosensitization
Authors: Wang Yu-shan , Huang Yi-Chun , Fong Weng-Lam , Chi Mau-Shin , Chi Kwan-Hwa 
Published: August 2012

Abstract
Chemoresistance is the main obstacle of successful cancer therapy. Autophagy may either enhance cancer cell death or activate chemoresistance. Simultaneous pushing and blocking of autophagy may be a valid strategy for overcoming drug resistance and improving responses. We hypothesized that simultaneous forcing hepatoma cells synchronized in a pro-autophagic status by rapamycin while blocking the final autophagic pathway by chloroquine is an example of synthetic lethality in synergism. Co-administration of the chemotherapeutic agents with rapamycin and chloroquine in 3 hepatoma cell lines have all demonstrated synergistic effects including 5-fluorouracil, navelbine, taxotere or cisplatin. Increasing doses of rapamycin and chloroquine resulted in a significant decrease of ED50 of different chemodrugs. Althrough hepatoma cell lines expressed difference status of autophage during various chemodrug treatments, co-administration of rapamycin and chloroquine could synchronize them on the pro-autophagic status while preveting them ensuring to the final autophagic status in all cell line tested. The combination of rapamycin and chloroquine and chemotherapeutic agents resulted in increased apoptotic cell death compared to chemotherapeutic agents alone. All of the observed synergistic chemosensitization effect from combination of chloroquine and rapamycin is more obvious than either agent alone. In vivo experiments are underway. If these synergistic effects can be reproduced in vivo, the combination of rapamycin and chloroquine may provide a valid reversing resistance strategy in treatment refractory cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5611. doi:1538-7445.AM2012-5611
Abstract 5612: The PI3K/Akt inhibitor LY294002 reverses BCRP/ABCG2-mediated drug resistance without BCRP translocation
Authors: Imai Yasuo , Yamagishi Hidetsugu , Ueda Yoshihiko 
Published: August 2012

Abstract
Cellular responses toward cytotoxic drugs are influenced by cross-talk between oncogenic signals and resistance mechanisms. Inhibition of the PI3K/Akt pathway is effective in sensitizing cancer cells of various organs, although the mechanisms have largely remained to be elucidated. Breast cancer resistance protein (BCRP)/ABCG2, a drug efflux pump, confers resistance to multiple anticancer agents such as SN-38 and topotecan. Previous studies reported that inhibition of the PI3K/Akt pathway, by gene knockout or PI3K inhibitors, modulated BCRP-mediated drug transport via BCRP translocation in hematopoietic stem cells, renal polarized cells, and glioma stem-like cells of mammals. In this paper, we tested reversing effects of PI3K inhibitors, LY294002 and wortmannin, on BCRP-mediated anticancer drug resistance of human cancer MCF-7 and A431 cells. LY294002 definitely reversed BCRP-mediated SN-38 and topotecan resistances but wortmannin did not. LY294002 treatment affected neither total nor cell surface BCRP levels by western blotting and flow cytometry but blocked BCRP-mediated topotecan efflux in a dose-dependent manner. Immunohistochemical analyses also demonstrated unchanged cellular BCRP distribution. BCRP overexpression in MCF-7 and A431 cells did not confer LY294002 resistance, suggesting that LY294002 would not be a transported substrate of BCRP. LY294002 is a derivative of quercetin, a member of flavonoid. Taken together, these results suggest that LY294002 inhibits BCRP-mediated drug transport not by BCRP translocation through the PI3K/Akt signal but putatively as a competitive inhibitor in a major subset of cancer cells. Due to its dual effects, LY294002 could be a lead compound for developing more effective and tolerable reagents for cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5612. doi:1538-7445.AM2012-5612
Abstract 5615: Combination therapy for chronic myelogenous leukemia: Targeting the BCR-ABL coiled-coil domain and other pathways for synthetic lethality
Authors: Woessner David W. , Lim Carol S. 
Published: August 2012

Abstract
Single-agent tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) has been largely effective in keeping the disease at bay. However, resistance to therapy and persistence of a subset of leukemic cells demonstrate the necessity for multiple-agent therapy. We have developed a unique interfering peptide, CCmut2 (Dixon et al., JBC 2011) able to disrupt BCR-ABL dimers. This disruption of trans-auto phosphorylation exacts its activity via the coiled-coil domain in BCR, but leads to an overall similar effect as TKIs - induction of apoptosis and reduction in proliferation. Here we detail the results of this peptide (delivered as a gene and transcribed in vitro) in combination with small molecule or biologic agents. The secondary agents include: chloroquine which is used to inhibit lysosomal acidification and block cellular macroautophagy; zileuton, a specific inhibitor of arachidonate 5-lipoxygenase (Alox5) known to enhance the proliferative capacity of CML cells; and GO-201, an interfering peptide targeting MUC-1, a known oncogene expressed in CML cells. These agents in combination with CCmut2 were hypothesized to improve therapeutic potency and enhance leukemia-specific cytotoxicity. All assays were performed in BCR-ABL expressing K562 cells in vitro. Western blots confirming knockdown of the autophagy gene ATG7, Alox5, and MUC-1 using shRNA were carried out. The autophagy pathway was further validated by blotting for autophagic microtubule-associated protein light chain 3 (LC3) conversion from LC3-I to LC3-II following combination therapy with CCmut2 and chloroquine. Transformative ability of K562 cells was evaluated using a methylcellulose colony forming assay following co-transfection with CCmut2 and a shRNA. Next, the specific drugs targeting these pathways were also used in combination with the CCmut2 and assessed for apoptotic potential using caspase 3/7 activity and DNA segmentation. Proliferation was investigated using trypan blue exclusion and transformative ability was further assessed with multi-drug combinations. MUC-1 inhibition in combination with CCmut2 resulted in a potent combination in K562 cells. Other combinations hinted at an additive or synergistic enhancement of apoptosis and reduction in proliferation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5615. doi:1538-7445.AM2012-5615
Abstract 5619: Drugging the “undrugable” DNA-binding domain of STAT3 for inhibition of cancer cell migration and invasion
Authors: Huang Wei , Zhang Jian-Ting 
Published: August 2012

Abstract
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors, and its activation is associated with high histological grade and advanced cancer stage. STAT3 has been shown to play important roles in multiple aspects of cancer aggressiveness including migration, invasion, survival, self-renewal, angiogenesis, and tumor-cell immune evasion by regulating the expression of multiple downstream target genes. Thus, inhibiting STAT3 promises an attracting strategy for treatment of advanced tumors with metastatic potential. Recently, using in-silico screening of a virtual compound database by docking onto the DNA-binding site of human STAT3, our laboratory identified specific STAT3 inhibitors that can disrupt DNA binding activity of STAT3 and inhibit STAT3-dependent cancer cell proliferation. In this study, we further characterized these STAT3 inhibitors and demonstrated that these inhibitors suppressed migration and invasion of both breast and lung cancer cells by inhibiting STAT3-dependent expression of metalloproteinase-2, -9 and vascular endothelial growth factor which are known to promote and enhance tumor metastasis. Taken together, we conclude that it is possible to inhibit STAT3 by targeting its DNA binding domain for discovery of anticancer therapeutics and for treatment of metastatic cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5619. doi:1538-7445.AM2012-5619
Abstract 5621: MicroRNA 203 modulates glioma cell migration and invasion by targeting ROBO1
Authors: Lakka Sajani S. 
Published: August 2012

Abstract
MicroRNAs (miRNAs) regulate mRNA stability and protein expression, and certain miRNAs have been demonstrated to act either as oncogenes or tumor suppressors. A potential role for miRNAs in malignancy has been suggested by the location of the genes for several miRNAs at sites of translocation breakpoints or deletions linked to a specific neoplastic state. Allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM and was thought to harbor multiple tumor suppressor genes associated with GBM, a region which also encodes mir-203. Real-time PCR and insitu hybridization showed decreased levels of mir203 expression in anaplastic astrocytoma and glioblastoma tissues and cell lines. Exogenous expression of mir-203 using a plasmid expressing mir-203 precursor (pmir-203) suppressed cell invasion and migration in SNB19 glioblastoma cell line and 4910 xenograft cells. We determined that one relevant target of miR-203 was ROBO1, since miR-203 expression decreased mRNA and protein levels as determined by RT-PCR and western blot analysis. Moreover, cotransfection experiments using luciferase-based transcription reporter assay have shown direct regulation of ROBO1 3α-UTR regions by miR-203 which was significantly abrogated when mutating the predicted miR-203 seed regions in the pMIR-REPORT UTR constructs, thereby validating the direct interaction between miR-203 and the ROBO1 3α-UTRs. Concordantly, over expressing ROBO1 expression construct with no mir-203 binding site blocked pmir-203 mediated suppression of migration and invasion. Taken together these studies demonstrate that up regulation of Robo1 in response to the decrease in mir-203 in glioma cells is responsible for glioma tumor cell migration and invasion.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5621. doi:1538-7445.AM2012-5621