bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C3: Validation and fitness testing of a quantitative immunoassay for HIF1α in biopsy specimens.
Authors: Kinders Robert J. , Park Sook Ryun , Khin Sonny , Hollingshead Melinda G. , Parchment Ralph E. , Tomaszewski Joseph E. , Doroshow James H. 
Published: June 2012

Abstract
HIF1α is an important marker of hypoxia in human tumors that is altered in a number of cancers, but a reproducible method to determine changes in HIF1α protein expression in human tumor biopsy specimens has not been available. HIF1α is being used as a pharmacodynamic marker in a clinical trial of metronomic Topotecan (CTEP# 8610, 9534). However, an important limitation for studying the response of HIF1α to cancer therapeutic agents is the lability of the protein, in the presence of oxygen, upon collection of the sample. We have devised a method of specimen collection, handling and extraction that preserves and stabilizes HIF1α levels in tumor biopsies. Employing this specimen handling method allowed validation of a two-site immunoassay for HIF1α quantitation in solid tissue extracts, such as tumor biopsies. Intra-assay variability was less than 10% and inter-assay variability was less than 20%. Accuracy, assessed by spike recovery, was 100 +/− 10%. HIF1α readings declined linearly with decreasing sample load over a range of 1 to 10 μg protein per well. HIF1α is being used as a pharmacodynamic marker in a clinical trial of metronomic Topotecan, so fitness for purpose was demonstrated by quantifying a reduction in HIF1α protein levels following topotecan treatment of a xenograft model. HIF1α was also demonstrated to be upregulated under low oxygen tension culture conditions in DU145 human prostate cancer cells. The HIF1α immunoassay is currently being transferred to the NCI's National Clinical Target Validation Laboratory for use in support of NCI-sponsored early clinical trials. This Research has been funded with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C3.
Abstract C41: Analysis of Her-2/neu status in brain metastases of breast cancer.
Authors: Rotin Daniil 
Published: June 2012

Abstract
Introduction: Breast carcinoma is the second common type of cancer metastasizing into the brain. Although the frequency of Her-2 positive primary breast tumors is no more than 30%, a higher occurrence of brain metastases has been reported for patients with positive Her-2/neu primary tumors. We investigated here expression of Her-2 protein and amplification of Her-2 gene in brain metastasis tissues of breast carcinoma patients.
Patients and Methods: FFPE tumor tissues were obtained from consented patients treated with surgery at the NN Burdenko Neurosurgery Institute in 2004–2007. Total of 42 cases of brain metastases (BM) with breast tissue origin were evaluated. Solitary BM occurred in 59% (16/27) patients, while multiple metastatic lesions were observed in 41% (11/27) patients. The median age was 53 (range 29 − 73 years). Her-2/neu gene amplification was analyzed by fluorescent in situ hybridization (FISH). Levels of protein expression were detected by immunohistochemistry (IHC) according to the DAKO HercepTest grading system. Membranous staining intensiveness was estimated by a semi-quantitative method (from 0 to 3+). Cases with Her-2 IHC expression score of 2+ were reconfirmed by FISH analysis. Statistical analysis was done using STATISTICA 6.0 software.
Results: Over-expression of Her-2 protein was observed in 50% (21/42) cases, while only in 7% (3/42) cases level of HER-2 protein was graded as negative (scores 0 and 1+). In 43% (18/42) cases IHC score was scored as 2+, and for those cases HER-2/neu gene amplification was performed using FISH analysis. Amplification of Her-2/neu was detected in 72% (13/18) cases in that group. Over-expression of Her-2/neu was similar in tissues from patients with a single metastatic lesion (63% (10/16) cases) compared to that of patients with multiple brain metastases (60% (25/42) of cases).
Conclusions: Despite relatively lower incidence in primary tumors, Her-2/neu positive breast cancer tumors prevail in breast cancer brain metastases (about 60%), perhaps attributing to the higher malignant potential of such tumors. We found no difference in Her-2/neu protein expression levels in patients with single and multiple brain metastases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C41.
Abstract C51: Molecular markers, prognosis, and efficacy of adjuvant anthracyclines in breast cancer.
Authors: Ali Alaa M. G. , Provenzano Elena , Abraham Jean , Driver Kristy , Bartlett John M.S. , Munro Alison , Poole Christopher John , Hiller Louise , Dunn Janet , Twelves Christopher , Earl Helena Margaret , Caldas Carlos , Pharoah Paul 
Published: June 2012

Abstract
Background: Molecular tumor markers can be used to classify breast cancer into sub-types that have distinct survival patterns. It is not known whether these sub-types respond differently to adjuvant chemotherapy. The purpose of this study was i) to evaluate the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate, and fluorouracil (CMF) with ECMF (epirubicin and CMF) and ii) to evaluate whether the sub-types were predictive of the added benefit of epirubicin in these trials.
Methods: We classified the tumors into six intrinsic sub-types using data generated from tumor tissue microarrays that were stained and scored for ER, PR, HER2, EGFR and CK5/6. We used Cox regression to compare relapse-free survival (RFS), breast cancer specific survival (BSS) and overall survival (OS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup.
Results: IHC data were available for 1725 cases of whom 805 were luminal 1-basal negative, 153 were luminal 1-basal positive, 174 were luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the sub-types were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy. In particular, the luminal 1-basal negative tumors were associated with the best prognosis during the five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33 percent relative risk reduction for OS compared to CMF. There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P=0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from epirubicin being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21–0.73) and the smallest being in luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64–1.16).
Conclusion: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer sub-types show distinct behaviour with differences in short and long term survival. These differences seem to be independent of the type of chemotherapy - the benefit of ECMF over CMF was statistically similar in all disease sub-types.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C51.
Abstract C52: Enhancing the activities of endogenous antibodies.
Authors: Alley Stephen , Benjamin Dennis , Emmerton Kim , Zhang Xinqun , Law Che-Leung , Okeley Nicole , Senter Peter 
Published: June 2012

Abstract
Many monoclonal antibodies (mAbs) exhibit activity through antibody dependent cellular cytotoxicity (ADCC), due to the binding interactions between the Fc portion of the mAb and Fc RIIIa on natural killer cells, macrophages and neutrophils. The strength of this interaction is affected by the glycosylation pattern at Asn-297 on mAb heavy chains. Defucosylated mAbs and mAbs with bisecting N-acetylglucosamine carbohydrates bind to Fc RIIIa with higher affinities, have more pronounced ADCC activities, and have demonstrated promising in vitro and in vivo activities. We have described a novel method for generating such mAbs involving the addition of simple fucose derivatives to the culture media of antibody-producing cell lines. This leads to the production of defucosylated mAbs with significantly (20–50 fold) increased ADCC activities, while minimally impacting production and cell viability. Generation of sugar engineered antibodies in this manner is distinguished from other technologies in that there is no need for genetic engineering and cell line modification. In addition, the technology has unique in vivo applications for endogenous production of defucosylated antibodies with high affinity binding to mouse Fc receptors. Here, we show for the first time that immunocompetent mice generate defucosylated antibodies when orally administered fucose derivatives such as fluorofucose. There were no apparent toxicities associated with treatment with fluorofucose at doses that led to greater than 90% defucosylation of circulating antibodies, Applications for these novel findings will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C52.
Abstract C64: Antitumor activity of GBR 500, a monoclonal VLA-2 antibody.
Authors: Hou Sam , Mancini Laura , Pesenti Enrico A. , Mottl Harald 
Published: June 2012

Abstract
VLA-2 is the alpha2beta1 integrin which mediates interactions of cells with collagens, laminin and other extracellular matrix components. In tumor cells, VLA-2 has been described to be involved in neovascularization, tumor-stroma interactions and metastasis.
The objective of this study was to assess the potential of VLA-2 as a target in a range of tumor models.
We used GBR 500, a monoclonal IgG4 antibody directed against the alpha2 subunit of the alpha2beta1 integrin heterodimer. The antibody binds to human but not to mouse VLA-2. GBR 500 is currently undergoing clinical phase I studies.
We first characterized the expression of VLA-2 in a set of 96 commonly used human cancer cell-lines from different tissues/organs (including colorectal, skin, breast, prostate, pancreas, lung, cervix, kidney, ovary, CNS, bone, liver, thyroid, and blood) and screened for growth inhibition in solid tumor subcutaneous xenografts.
In an orthotopic mouse xenograft model using a DU145-luc cell line we explored the importance of VLA-2 for tumor growth in a physiological setting. We finally assessed the effect of VLA-2 antagonism on metastasis in a PC-3 luc metastasis model.
Results: VLA-2 inhibition leads to modest growth reduction in subcutaneous xenografts. In the orthotopic xenograft stronger tumor growth inhibition was achived. The strongest tumor growth inhibition effects were achieved in the mestastasis model.
Conclusion: According to our finding growth inhibition of tumors by VLA-2 inhibition increases with increased stroma exposition
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C64.
Abstract C66: Role of mTORC1 and mTORC2 in multiple myeloma and their targeting with CC214.
Authors: Pandiella Atanasio , Chen Xi , Ocio Enrique M. , Diaz-Rodriguez Elena , Lopez-Girona Antonia , Chopra Rajesh , Miguel Jesus San 
Published: June 2012

Abstract
The Mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase which regulates cell growth, proliferation and metabolism and plays those roles by forming two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Deregulation of mTOR pathway is common in different cancers including multiple myeloma (MM). Moreover, recent studies on the role of Deptor and Grb10 in myeloma cells emphasize the importance of mTOR pathway in MM. However, a clear identification of the role of mTORC1 and mTORC2 in myeloma cells has not been achieved due to the lack of inhibitors specifically targeting these two branches. In this study, we show that both mTORC1 and mTORC2 are constitutively active in a panel of MM cell lines. Moreover, we analyzed the basal status of both branches in a cohort of MM patients (n=40) by means of multiple parameter flow cytometry using phospho-S6 and phospho-Akt as readouts for activation of mTORC1 and mTORC2, respectively. To explore the contribution of mTORC1 or mTORC2 route to the proliferation of MM cells, we employed the RNA interference of Raptor and Rictor through infection of OPM2 and MM1S with shRNA expressing lentivirus, and found that downregulation of Raptor substantially decreased cell proliferation to a higher extent than Rictor and knockdown of mTOR fully prevented cell proliferation. These data suggested a major role of mTOR pathway in the regulation of myeloma cell proliferation and support the idea of mTOR as a target for anti-myeloma therapy. For this reason, we evaluated the novel mTOR inhibitor CC214. This drug inhibited cell growth in all the cell lines tested, induced cell cycle arrest at G0/G1 by altering cell cycle related proteins, and provoked apoptosis evident by the cleavage of caspases and PARP. Besides, CC214 induced cell death in plasma cells in ex vivo culture of freshly isolated cells from bone marrow of MM patients. These results suggest that mTOR inhibitors may be of help in the future treatment of myeloma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C66.
Abstract C83: SiRNA screen identifies a G2-M signaling node as a novel therapeutic target in medulloblastoma.
Authors: Vibhakar Rajeev , Harris Peter , Venkatraman Sujatha , Alimova Irina , Foreman Nicholas 
Published: June 2012

Abstract
Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Although cisplatin chemotherapy and radiation have been the cornerstones of medulloblastoma intervention for over 20 years, the outcomes of these highly cytotoxic treatments are far from optimal, and there is increasing evidence that they cause long-term problems such as neurocognitive deficits and secondary tumors, even in patients with a good initial response. Thus, there is a critical need for more effective therapies to combat this disease.
To approach this problem we investigated protein kinase function in medulloblastoma using RNAi combined with genomic methods. First, we performed a kinome-wide siRNA screen and identified a cohort of genes that mediates medulloblastoma cell viability. These include a signaling node of kinases that are key components of the G2-M transition including, Aurora Kinase A, Aurora Kinase B, Plk1, Wee1, Nek2 and Mps1. Clearly the G2-M transition is critical for medulloblastoma cells, so kinases required for the process are potentially important therapeutic targets. We subsequently validated PLK1 and WEE 1 as bona fide therapeutic targets. Small molecule inhibitors of WEE 1 and PLK1 potently inhibited medulloblastoma cell growth and sensitized cells to radiation.
In conclusion, using siRNA screens we identified novel therapeutic targets for medulloblastoma therapy
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C83.
Abstract C86: DC120, a novel and potent inhibitor of AKT kinase, induces tumor cells apoptosis and suppresses tumor growth.
Authors: Deng Rong , Chang Shao-hua , Tang Jun , Feng Gong-Kan , Yang Fen , Qin Juan , Ding Ke , Zhu Xiao-Feng 
Published: June 2012

Abstract
PKB/AKT kinase is the core component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway which is one of the most frequently hyperactivated signaling pathways in human cancers. We designed and synthesized a series of 2-pyrimidyl-5-amidothiazole coumpounds based on the ATP binding site of AKT kinase, and the most potent compound DC120 was identified to inhibit AKT kinase activity in vitro with EC50 of 153nM by a FRET-based Z'-Lyte assay. Then the growth inhibition of DC120 on human CNE2 and MDA-MB-453 cell lines was tested in vitro. The results showed DC120 could obviously inhibit the proliferation of these cancer cell lines via induction of apoptosis, with the evidence of increasing sub-G1 cells, characteristic morphologic changes of apoptosis in the nucleus, and cleaved caspase-3 and PARP. Further study showed that MDA-MB-453 cells transfected with constitutively activated AKT1 were more sensitive to DC120, while CNE2 cells with knock-down of AKT1 expression by shRNA were more resistant to DC120. More importantly, DC120 attenuated the phosphorylation levels of FKHR, FKHRL1, GSK-3 and mTOR in a dose-dependent and time-dependent fashion, and led to an increase in the nuclear accumulation of exogenous FKHR in cancer cells. Additionally, the in vivo experiments showed DC120 at 20 mg/kg/qd remarkably inhibited the CNE2 xenograft tumor growth with the T/C value of 36.1%, accompanied by increasing TUNEL-positve cells in tumor sample. These data provide validation for the development of DC120 to treat cancers displaying elevated levels of AKT.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C86.
Abstract C88: A novel multiplex RNA in situ hybridization (ISH)-based method for circulating tumor cell detection with demonstrated clinical utility for metastatic breast cancer.
Authors: Payne Rachel E. , Wang Fay , Su Nan , Krell J. , Zebrowski A. , Yague Ernesto , Ma Xiao-Jun , Luo Yuling , Coombes R. Charles 
Published: June 2012

Abstract
Purpose: Sensitive and specific detection of circulating tumor cells (CTCs) in a blood sample is required for realizing the full potential of CTCs as prognostic and predictive factors. Current approaches of CTC detection are largely ineffective, and are dependent on the presence of differential epithelial protein markers or upon crude morphological characteristics like cell size differences between CTCs and blood cells. These combined approaches do not detect all relevant CTCs due to their significant heterogeneity. The objectives of this study are to develop and characterize a novel RNA in situ hybridization (ISH)-based CTC detection system called CTCscope, and to demonstrate its potential clinical utility in metastatic breast cancer patients.
Experimental Design: Cultured cells of different cancer cell lines were spiked into whole blood, which was used as a model system for CTCscope development. A novel ultrasensitive fluorescent RNA-ISH method was used to detect mRNA transcripts of a multitude of tumor markers at single-cell resolution. To demonstrate feasibility of CTC detection in patient blood, duplicate blood samples were collected from 45 metastatic breast cancer patients with informed consent for CTC analysis by the newly developed CTCscope system and the CellSearch system. Association of CTCs with tumor marker CA15–3 and progression-free survival (PFS) was assessed.
Results: CTCscope detected mRNA transcripts of 8 epithelial tumor markers and 3 epithelial-mesenchymal-transition (EMT) markers, and resulted in increased sensitivity for CTC detection. CTCscope was used to detect CTCs without enrichment, and did not result in false positives from detection of apoptotic or dead cells. In patient blood samples, CTCs detected by CellSearch but not CTCscope were positively correlated with CA15–3 levels. CTCs detected by either CTCscope or CellSearch predicted PFS, but only CTCs detected by CTCscope remained significantly associated with PFS (hazard ratio 2.01, 95% CI 1.14–3.92, p=0.038) after adjusting for CA15–3 levels.
Conclusions: The CTCscope assay may offer unique advantages over existing CTC detection approaches. By enumerating and characterizing only viable CTCs, CTCscope may provide additional prognostic and predictive information.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C88.