bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1292: Broad vascular distribution of Neuropilin-1 and its ligands in human tumors
Authors: Mak Judy , Tong Raymond , Koch Alexander , Kowalski Joe , Frantz Gretchen , Peale Franklin , Watts Ryan , Bagri Anil 
Published: February 2011

Abstract
Neuropilin-1 (NRP1) is a multi-domain transmembrane receptor that is important for the development of the nervous and vascular systems and has been implicated in modulating various aspects of tumor biology. We have previously shown that an antibody directed against NRP1 inhibits tumor growth and reduces tumor angiogenesis, as a single agent and more potently in combination with anti-VEGF. Currently, anti-NRP1 is in evaluation in early clinical studies. Therefore, understanding the expression pattern of Nrp1 and its relevant ligands in human tumor samples is of critical importance. To this end, we first evaluated the binding of a number of putative ligands that have been suggested to interact with NRP1 in the literature, and furthermore to understand which of these are biochemically or functionally inhibited by our anti-NRP1. We found that members of the semaphorin and VEGF families, but not HGF bind to NRP1. However, only binding and function of specific ligands from the VEGF family are inhibited by anti-NRP1. Additionally, we evaluated the expression pattern of NRP1 in human tumor samples from a number of different tumor types, including breast, colorectal, lung, ovarian, pancreatic, prostate and renal cancer. NRP1 is broadly expressed in the vasculature of most cases of all these tumor types. Additionally, NRP1 is also variably expressed by tumor cells and other stromal elements in a more variable manner that is tumor type dependent. These results suggest that NRP1 is a potentially important therapeutic target in many different tumor types.
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 1292.
Abstract 1311: ATR inhibition sensitizes p53-deficient cancer cells to chemotherapeutic drugs
Authors: Sangster-Guity Niquiche , Conrad Bogdan H.M. , Bunz Fred 
Published: February 2011

Abstract
PURPOSE: We sought to determine whether genetic inhibition of the ATR kinase would preferentially sensitize p53-deficient cancer cells to therapeutic agents that cause replication stress. EXPERIMENTAL PROCEDURES: Previous studies have shown that p53-deficient cancer cells harboring hypomorphic ATR alleles are highly sensitive to DNA damaging agents and DNA replication inhibitors that are commonly used in the clinic. We hypothesize that p53-dependent cell cycle checkpoints would prevent damaged, ATR-deficient cells from entering S-phase and mitosis, and thereby enhance cell survival. To test this hypothesis, we used a gene targeting approach to knock-in wild type p53 into cells with wild type and hypomorphic ATR alleles. The combined effects of ATR and p53 were determined by clonogenic survival assays, flow cytometry and analysis of apoptotic proteins. SUMMARY: RNAi-mediated knockdown of ATR in p53-deficient cells caused reduced survival after cisplatin treatment, compared with knockdown of ATR in isogenic p53-proficient cells. To unambiguously test whether ATR inhibition preferentially sensitizes p53-deficient cancer cells, we used a knock-in vector to replace a p53-mutant allele with a wild type allele. Homologous recombinant cells expressed wild type p53 protein and the p53 target proteins p21 and p53R2, demonstrating restoration of a functional p53 pathway. Knock-in of wild type p53 restored the G1/S checkpoint induced by ionizing radiation. Most significantly, genetic restoration of the p53 pathway rescued the survival defect of the ATR-deficient cells in response to chemotherapeutic drugs. CONCLUSIONS: Our data provide genetic evidence that p53 and ATR function synergistically to enhance the survival of human cancer cells treated with agents that cause DNA replication stress. We propose that pharmacologic inhibition of ATR would cause enhanced killing of cells with loss of p53 function following treatment with DNA replication inhibitors and DNA crosslinking agents, thereby increasing their therapeutic index.
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 1311.
Abstract 1325: PCI-5002 leads to enhanced radiosensitization via induction of necrotic cell death by promoting autophagy in non-small cell lung tumor xenograft model
Authors: Jung Dae Kwang , kim kwang woon , Lu Bo 
Published: February 2011

Abstract
Purpose: We previously showed that Bax/Bak inhibition induces autophagy and promotes radiosensitivity in vitro and in vivo. Therefore, we further investigated the specific mechanism by which radiation triggers necrotic cell death via autophagy in H460 cells treated with PCI-5002, water-soluble zinc ionophores, in vitro or in vivo.
Methods: Clonogenic assay was used to determine radiosensitivity. H460 lung cancer xenografts was generated and immunohistochemistry (IHC) was performed on tumor sections for tumor cell proliferation (Ki67 staining), angiogenesis (von Willebrand Factor staining), and apoptosis (cleaved caspase-3 antibody staining). Autophagy was determined by p62 protein, which is named sequestosome 1(SQSTM1) and links polyubiquitinated proteins to the autophagic machinery in vivo and punctuate localization of GFP-LC3 fusion protein, which observed under a confocal fluorescence microscope in vitro. Necrosis was determined with HMGB1 release and Propidium lodide (PI) staining.
Results: The PCI-5002 markedly enhanced sensitivity of MEF WT cells to radiation (DER=1.43, p=0.003) in clonogenic assay. This enhanced radiosensitization was associated with an increase in characteristic punctuate localization of GFP-LC3 when was blocked a cleaved caspase-3 in MEF WT cells treated with PCI-5002, suggesting that autophagy was induced simultaneously. We found that PCI-5002 with radiation showed a dramatically enhanced sensitivity of H460 cells to radiation (DER=1.92, p=0.001) in clonogenic assay, and tumor growth delay in a mouse hind limb xenograft model in vivo, and was well tolerated compared to control. In addition, the concurrent administration of PCI-5002 and radiation in vivo significantly decreased cell proliferation and vascular density compared to radiation alone. Consistent with the in vitro results, treatment both PCI-5002 and radiation showed a dramatically increase in HMGB1 as a marker for Necrosis and a significant decrease in p62 protein level for detecting autophagic flux in the lung tumor xenograft model.
Conclusions: These results suggest that induction of necrosis via promotion of autophagy may be utilized as a novel strategy to enhance radiation therapy in lung cancer.
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 1325.
Abstract 133: Effects of iASPP on paclitaxel-mediated mitotic catastrophe and chemoresistance in ovarian cancers
Authors: Jiang Li Li , Siu Michelle KY , Wong Oscar GW , Tam Kai Fai , Lu Xin , Lam Eric WF , Ngan Hextan YS , Le Xiao Feng , Wong Esther SY , Monteiro Lara J. , Chan Hoi Yan , Cheung Annie NY 
Published: February 2011

Abstract
Purpose: In this study, for the first time, we aimed to investigate the expression profile of iASPP in ovarian epithelial tumor in association with clinicopathological parameters. In vitro effect of iASPP on paclitaxel chemosensitivity will also be investigated.
Materials and Methods: Expression and amplification status of iASPP was examined in 140 clinical samples and 16 ovarian cell lines using immunohistochemistry, immunoblotting and quantitative real-time PCR, and correlated with clinicopathological parameters. Changes in proliferation, mitotic catastrophe and apoptosis in ovarian cancer cell lines of different p53 status following paclitaxel exposure were also analyzed using TUNEL assay, MTT assay and immunofluorescence.
Results: By immunohistochemistry and quantitative PCR, significantly higher protein and mRNA levels of iASPP was found in ovarian cancers when compared with borderline and benign ovarian tumour samples. Higher iASPP expression was also found in ovarian cancer cell lines than normal ovarian epithelial cell lines. Higher iASPP expression was significantly associated with carboplatin and paclitaxel chemoresistance (P=0.04), shorter overall (P=0.003) and disease-free survival (P=0.001). Multivariate analysis confirmed iASPP expression as an independent prognostic factor. Increased iASPP mRNA expression was significantly correlated with its gene amplification (P=0.018), suggesting that gene amplification contributes to overexpression of iASPP in ovarian caner. By in vitro assay, we demonstrated that iASPP overexpression in ovarian cancer cells conferred resistance to paclitaxel by reducing mitotic catastrophe in a p53-independent manner via activation of separase whilst knockdown of iASPP enhanced paclitaxel-mediated mitotic catastrophe through inactivating separase. Both securin and cyclin B1/CDK1complex were involved in regulating separase by iASPP. Conversely, overexpressed iASPP inhibited apoptosis in a p53-dependent mode.
Conclusion: Our findings suggested that iASPP may be explored as a potential prognostic marker and a novel molecular target for chemotherapy of ovarian cancers, especially in patients with chemoresistant or recurrent cancers.
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 133.
Abstract 1365: Novel anti-angiogenic peptides as potential therapeutic agents in combination with chemotherapy for breast cancer
Authors: Rosca Elena V. , Koskimaki Jacob E. , Popel Aleksander S. 
Published: February 2011

Abstract
Breast cancer is one of the most commonly diagnosed malignancies in women. Despite the intensive ongoing research it is estimated that approximately 200,000 new diagnoses will be made in 2009 and 40,000 deaths will occur due to this disease. Angiogenesis, the development of vessels from pre-existing microvasculature, is an essential component of tumor progression and has emerged as a therapeutic target for anti-angiogenic therapies in cancer. The process is controlled by a balance between endogenous pro- and anti-angiogenic factors, and involves numerous interactions among several cell types including proliferation, invasion, and migration. Bevacizumab (Avastin, Roche/Genentech), an anti-VEGF monoclonal antibody, has been approved by the FDA for several types of cancer; however, in the case of breast cancer its effect on the overall survival is only marginal.
Our laboratory has established a systematic bioinformatics approach to identify short novel anti-angiogenic peptides from natural proteins. These peptides belong to different classes (i.e. thrombospondin containing domain, collagen IV, chemokines etc) and in vitro experiments demonstrated their anti-angiogenic potential through inhibition of proliferation and migration of human endothelial cells. Moreover, several peptides have demonstrated efficacy in suppressing tumor growth when delivered as daily intraperitoneal injections in a mouse orthotopic breast cancer model. The repression was associated with a decrease in tumor microvasculature and an increase in necrotic core of the tumors (Koskimaki et al., 2009). The top performing candidate (a 24 amino acid peptide belonging to the collagen IV family) was further modified to find the optimal sequence for possible translation to clinical applications. Several truncations and substitutions of cystines by amino alpha-butyric acid were developed. The candidates were screened in in vitro proliferation assays and the top performer (full sequence length with substituted cystines) was tested in vivo using the orthotopic breast cancer model. This candidate demonstrated no significant changes in activity from the parent peptide, however making it is more conducive for clinical translation. We also investigate its application in combination with a typical chemotherapeutic agent (paclitaxel) and confirmed no decrease in activity in comparison to single agent therapy. We have performed further characterization of the mode of action for this peptide to identify its target receptors; this enhances the translation potential of this candidate as an anti-angiogenic, non-VEGF targeting agent for therapy in breast cancer.
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 1365.
Abstract 1435: Functional expression of chemokine receptor, CCR10, in patients with gastric cancer
Authors: Bae Jae-Moon , Lee Jun Ho , Kook Myoung Cheorl 
Published: February 2011

Abstract
Objectives: There is increasing evidence that chemokines and chemokine receptors are causally involved in the metastasis of cancer. The aim of this study was to investigate the expression of chemokine receptors, CCR10, and its prognostic role in patients with gastric cancer.
Methods: We screened the expression of CCR10 in 12 gastric cancer cell lines using the semi-quantitative RT-PCR. The expression of CCR10 was confirmed using Western blot and flow cytometry analysis of twelve gastric cancer cell lines. The function of CCR10 was examined using migration and proliferation assays. Then the migratory response of CCR10 was blocked using blocking antibodies. Finally, the clinical significance of the chemokine receptors was explored using tissue microarray methods and immunohistochemical staining of specimens from 753 gastric cancer patients.
Results: We found that twelve out of twelve (100.0%) gastric carcinoma cell lines expressed a functional CCR10 for its ligand, chemokine CCL27 and CCL28, as demonstrated by the migration assays, and the migration was inhibited by anti-CCR10 antibodies. The clinical samples evaluated by immunohistochemical assay of tissue microarrays showed that CCR10-positive carcinoma cells were detected in 22 of 753 (2.9%) cases. We failed to show that the patients with CCR10-positive tumors had significantly poorer prognosis than did those with CCR10-negative tumors.
Conclusion: These results suggest that CCR10 and its ligands were associated with increased tumor migration in gastric cancer.
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 1435.
Abstract 151: Utilizing 3-D nuclear DNA methylation patterns for cell-based assays in epigenetic drug screening
Authors: Gertych Arkadiusz , Farkas Daniel L. , Tajbakhsh Jian 
Published: February 2011

Abstract
The reversibility of epigenetic modifications, such as cytosine methylation, has gained much attraction in cancer therapy, with an emphasis on the development of anti-cancer drugs with demethylating potential to primarily reestablish tumor- suppressor gene functionality. The interest in the development of novel epigenetic drugs has increased the demand for cell-based assays to evaluate drug performance in the important pre-clinical phases of drug screening. Ideally a demethylating drug should reduce hypermethylation of tumor-suppressor genes for their reactivation, without creating unwanted effects: i.e. the hypomethylation of heterochromatin, of which a large percentage occurs in repetitive elements and can lead to genome instability. We have recently developed 3D quantitative DNA Methylation Imaging (3D-qDMI), an image-cytometrical approach, that can measure spatial nuclear distributions of methylated cytosine (MeC) and global DNA (gDNA) in addition to the nuclear MeC load in a high-throughput and cell-by-cell fashion to verify unwanted effects such as increased heterochromatin hypomethylation and decondensation that involve large-scale chromatin reorganization visualized by high-resolution confocal microscopy. Our novel approach succeeded in tracking differential changes of higher-order DNA organization due to drug-induced demethylation on a genomic scale, in human and mouse cancer cells. Our study showed that the differential distribution patterns of these two classes of DNA have the potential to be utilized as signatures for the characterization of different demethylating agents such as 5-azacytidine and zebularine.
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 151.
Abstract 1632: Co-targeting mTOR and IGF-1R/IR results in synergistic activity against a broad array of tumor cell lines, independent of KRAS mutation status
Authors: Barr Sharon , Russo Suzanne , Buck Elizabeth , Epstein David , Miglarese Mark 
Published: February 2011

Abstract
The IGF-1 receptor (IGF-1R) and insulin receptor (IR) are known to couple via IRS-1 to the PI3K signaling axis. Upon activation, these receptor tyrosine kinases stimulate PI3K, initiating a cascade of ser/thr kinases, including mTOR. mTOR is associated with two complexes: mTORC1, rapamycin sensitive, and mTORC2, which does not bind rapamycin. Since mTOR functions downstream of IGF-1R and IR, it is thought that tumor cells sensitive to IGF-1R inhibition would also respond to mTORC1/mTORC2 inhibition. To test this hypothesis we evaluated the effects of OSI-906, a selective small molecule dual kinase inhibitor of IGF-1R and IR and OSI-027, a selective catalytic-site inhibitor of mTORC1/mTORC2, alone and in combination in cell proliferation assays using a broad array of tumor cell lines. Across multiple tumor types, cells with activating KRAS mutations were typically less sensitive to OSI-027 than those expressing wild-type KRAS. In contrast, mutant KRAS did not reduce sensitivity to OSI-906. Cell lines with activating mutations in PIK3CA or loss of PTEN were sensitive to OSI-027 but the presence of a concurrent mutation in KRAS decreased their sensitivity to OSI-027. In KRAS mutant cells, OSI-906 was more effective than OSI-027 at reducing phospho-AKT levels. Conversely, in tumor cell lines with wild-type KRAS cells, OSI-027 more effectively reduced phospho-AKT levels compared to OSI-906. Similar effects were observed in a pair of isogenic cell lines engineered to express either wild-type or mutant KRAS. The observation that tumor cell lines exhibit differential sensitivity to inhibitors of IGF-1R/IR or mTORC1/mTORC2 supports the concept that IGF-1R and IR can activate multiple pathways and are not limited to signaling through the mTOR axis. Also, mTOR is a central signaling hub which integrates signaling from multiple inputs, not only the IGF-1R/IR cascade. The combination of OSI-906 and OSI-027 synergistically inhibited the proliferation of cancer cell lines, including those expressing mutant KRAS. In some cases, the combination also resulted in synergistic induction of apoptosis. These data provide support for further exploration of the potential utility of combining OSI-906 (dual IGF-1R/IR inhibitor) with OSI-027 (dual mTORC1/mTORC2 inhibitor) for the treatment of human cancers, including those with activating mutations in KRAS.
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 1632.
Abstract 1723: Thiazolinediones (TZDs) mediate proliferation and cell cycle kinetics in ovarian cancer cells in a PPARγ-dependent and -independent manner
Authors: Al-Alem Linah F. , Southard Chase R. , Kilgore Michael W. , Curry Thomas E. 
Published: February 2011

Abstract
Ovarian cancer is the leading cause of death in women with gynecological malignancies and is often called the ‘silent killer’. Thus, new treatment targets are constantly being investigated. PPARγ (Peroxisome Proliferator Activated Receptor gamma) is a nuclear transcription factor that has been implicated in several diseases. However, little is known about PPARγ in ovarian cancer. Recently, PPARγ agonists such as the thiazolinediones (TZDs) have been studied for their potential use as a therapeutic treatment for cancer. In the present study, we investigated the effect of the four TZDs: Rosiglitazone (Rosi), Ciglitazone (CGZ), Troglitazone (TGZ), and Pioglitazone (Pio), on cell proliferation and PPARγ expression in an ovarian cancer cell line: Ovcar3. Treatment with 10 μM CGZ or TGZ for 24 hours decreased proliferation, whereas Rosi and Pio had no effect. We observed that this decrease in Ovcar3 cell proliferation is due to a higher fraction of cells in the G0/G1 stage of the cell cycle. In order to assess whether this was mediated by PPARγ, we investigated the effect of TGZ and CGZ on PPARγ mRNA, protein expression and activity. As Rosi and Pio had no effect on proliferation, only CGZ and TGZ were further investigated. CGZ and TGZ increased PPARγ mRNA expression in Ovcar3 cells (6.9 and 18.1 fold respectively). However, levels of PPARγ protein expression did not correlate with mRNA levels. Moreover, luciferase reporter assays showed that neither of the TZDs increased PPARγ activity. Ovcar3 cells were transfected with a PPARγ overexpression vector (WT) or a mutant dominant negative form of PPARγ (DN). Both CGZ and TGZ increased PPARγ activity when the receptor was over-expressed. Interestingly, the over-expression of WT in unstimulated cells caused an increase in reporter activity, indicating that these cells have the endogenous capacity to mediate PPARγ transactivation. Cells exhibited no changes in proliferation when transfected with the WT or DN forms of PPARγ. Also, the effect on proliferation was not impacted when CGZ or TGZ were added to the WT or DN transfected cells. These findings demonstrate that PPARγ agonists, CGZ and TGZ, stimulate PPARγ expression. However, the decrease in cell proliferation and increased cell cycle arrest seems to be due to both PPARγ dependent and independent mechanisms. These data suggest that the non-PPAR targets of TZDs need to be further investigated. (Supported by NIH RO1 CA 95609-01, and NCRR-P20-RR15592).
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 1723.