bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B292: HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway.
Authors: Jazirehi Ali R. , Kurdistani Siavash K. , Economou James S. 
Published: August 2014

Abstract
Modern immune therapies [PD-1/PD-L1 and CTLA-4 checkpoint blockade, adoptive cell transfer (ACT)] have remarkably improved the clinical treatment of metastatic melanoma. These modalities rely on the killing potential of cytotoxic T lymphocytes (CTL) as primary mediator of their anti-melanoma responses. The mechanisms of resistance to and the predominant cytotoxic pathway(s) employed by melanoma-reactive CTLs remain largely elusive. Moreover, strategies to bypass CTL-resistance are urgently needed in clinical melanoma therapy. We hypothesized that down-modulation of death receptors in addition to aberrant apoptotic signaling might confer resistance to death signals delivered by CTLs. To test this hypothesis, we used an in vitro model of resistant sublines generated from MART-1+/A*0201+ parental lines sensitive to MART-1 TCR transgenic CTL (F5 CTL) under serial F5 CTL-selective pressure. Here, we report that F5 CTLs mainly use the TNF-related apoptosis-inducing ligand (TRAIL) cytotoxic pathway, explicitly via DR5, in killing sensitive melanomas. Further, F5 CTL-resistance was due to DR5 down-regulation and abnormal ratio of anti- to pro-apoptotic molecules, both of which were reversed by the FDA-approved epigenetic modifier SAHA. Restoration of sensitivity by SAHA was confirmed using transgenic and patient-derived MART-1-specific CTLs, rhTRAIL and DR5 agonist Drozitumab. Mitochondrial destabilization and cytosolic release of apoptotic molecules was only evident by combination of SAHA and rhTRAIL or Drozitumab. These findings suggest that exposure to SAHA of immune-resistant melanomas can skew towards an intracellular pro-apoptotic milieu, increase death receptor expression, and overcome acquired immune-resistance.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B292.
Citation Format: Ali R. Jazirehi, Siavash K. Kurdistani, James S. Economou. HDACi immunosensitizes CTL-resistant human melanomas to adoptive cell transfer (ACT) by modulating TRAIL/DR5apoptotic pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B292.
Abstract B42: The study on molecular targets of classification of head and neck squamous cell carcinoma.
Authors: Chen Wantao , Cao Wei , Zhang Ping , Cui zhibin , Xu Qin , Wang Xu 
Published: August 2014

Abstract
Objective: Molecular classification are the basis for designing strategies of individual diagnosis, treatment and prediction of prognosis in head and neck sqamous cell carcinoma (HNSCC). The purpose of this study is to establish the methods of molecular classification, screen and validate the potential biomarkers, and identify the molecular targets of molecular pathological diagnosis, progressive and lymph node metastasis for HNSCC.
Methods: Based on previous study of gene expression profile on HNSCC, our research group preliminarily screened 78 HNSCC-related genes. In this present study, the mRNA expressions of 78 candidate genes were evaluated by real-time PCR in 240 tissues, including 120 HNSCCs and 120 independent normal mucosa and quantified according to an internal control β-actin. And the differentially expressed genes, aggressive-related genes and metastasis-related genes in HNSCC were selected and validated.
Results: 1. The gene expression profile signature “SPP1 et al.” was the optimal group as the differential genes between cancer and normal tissues (AUC:0.986,95% CI:0.961-0.997; sensitivity: 96.4%, specitivity: 94.74%). 2. The gene expression profile signature “CDK2 et al.” was the optimal group to predict the pathological grade (AUC: 0.811, 95% CI: 0.726 to 0.879; sensitivity: 86.7%, specitivity: 63.5%). And the gene expression profile signature “MMP7 et al.” was the optimal group to predict the histologic signs of severity (AUC: 0.749, 95% CI: 0.661 to 0.823; sensitivity: 60.3%, specitivity: 87.7%). 3. The gene expression profile signature “PDGFRA et al.” was the optimal group to predict lymph node metastasis (AUC: 0.769, 95% CI: 0.675 to 0.846; sensitivity: 71%, specitivity: 75%).
Conclusions: The gene-expression signatures validated in this study on molecular diagnosis, progressive and lymph node metastasis may be served as a potential biomarker of molecular diagnosis/molecular classification for HNSCC in future.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B42.
Citation Format: Wantao Chen, Wei Cao, Ping Zhang, zhibin Cui, Qin Xu, Xu Wang. The study on molecular targets of classification of head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B42.
Abstract B45: Gene expression alteration in chronic hypoxic MCF7 breast cancer cell line.
Authors: Zihlif Malek A. , Hamdan Feda' Hisham 
Published: August 2014

Abstract
Background: As solid tumors outgrow their vasculature, areas of low oxygen concentration arise where the oxygen demand surpasses supply. Hypoxia plays a significant role in tumor progression and aggressiveness. It is also implicated in therapy resistance to radiotherapy and chemotherapy.
Objective: The aim of this study is to characterize the changes in gene expression associated with chronic hypoxia in MCF7 breast cancer cell line with the goal of identifying a possible biomarker for hypoxia in breast cancer.
Methodology: Breast cancer cells (MCF7) were exposed to 8-hour hypoxic episodes (&lt;1% oxygen) three times a week for a total of 38 episodes. The alterations in gene expression were measured using the real-time based PCR array technology after 19 and 38 episodes of hypoxia and compared to normoxic cells. Chemoresistance of hypoxic cells toward doxorubicin was assessed using MTT cell proliferation assay.
Results: Marked gene expression changes were indentified after 19 and 38 episodes of hypoxia. Only few changes were common in both stages with most genes rebounding at the level of 38 episodes. A notable gene (HNF4A) has been up-regulated by 2 folds after 19 hypoxic shots and further up-regulated by 6.43 folds after 38 hypoxic shots. The half maximal inhibitory concentration (IC50) of doxorubicin in MCF7 cells has increased by 1.5 folds after 19 episodes of hypoxia and quadrupled after 35 episodes compared to normoxic cells.
Conclusions: This study provide evidence that exposing cells to prolonged periods of hypoxia (weeks) results in different expression changes than those induced by short-term hypoxia (&lt;72 hours). It also confirms induction of chemoresistance by chronic hypoxia. Finally, it proposes HNF4A as a potential biomarker for hypoxia in breast cancer and as a main player in the cellular response to chronic hypoxia.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B45.
Citation Format: Malek A. Zihlif, Feda’ Hisham Hamdan. Gene expression alteration in chronic hypoxic MCF7 breast cancer cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B45.
Abstract B53: Induction of cells with cancer stem cell properties from p53-deficient somatic cells.
Authors: Nishi Mayuko , Ryo Akihide 
Published: August 2014

Abstract
The tumor suppressor p53 prevents the initiation of tumor formation by inducing cell cycle arrest, senescence and apoptosis during the process of oncogenesis. Although p53 deficiency promotes the efficiency of somatic cell reprogramming to a pluripotent state upon the transduction of four reprogramming genes Oct4, Sox2, Klf4, and c-Myc, it often gives rise to induced pluripotent stem cells (iPSC) with cancer-like features. We attempted to generate cells with cancer stem cell (CSC) properties from p53-deficient mouse embryonic fibroblasts (MEFs) in vitro. The introduction of iPS reprogramming factors into p53-/- MEFs, followed by partial differentiation via embryoid body formation, transformed the bulk of cells into tumorigenic cells with CSC features. These transformed cells displayed a malignant phenotype and formed tumors of multiple lineages when injected into immunocompromised mice. Immunohistochemical analysis revealed the presence of epithelial (E-cadherin), mesenchymal (Vimentin) and myogenic (Desmin) positive cells in the tumor tissues. These transformed CSC-like cells can be maintained in regular cell culture media in vitro with 10% fetal bovine serum, permitting easy manipulation and amenability to large-scale drug screening. Our current approach could therefore provide a valuable basis for the further analysis of CSC characteristics and drug development strategies designed to target CSCs.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B53.
Citation Format: Mayuko Nishi, Akihide Ryo. Induction of cells with cancer stem cell properties from p53-deficient somatic cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B53.
Abstract B6: CEA affects tumor- angiogenesis via integrin-dependent activation of endothelial cells.
Authors: Prager Gerald W. , Braemswig Kira , Poettler Marina , Zieleinski Christoph 
Published: August 2014

Abstract
CEA, first identified in 1965 by Phil Gold and Samuel O. Freedman, is aberrantly overexpressed by up to 70% of human cancers. In clinical use as extracellular marker for monitoring adenocarcinoma growth as well as treatment efficacy, CEA has become included into the routine practice of clinical oncology. In addition to its’ clinical relevance, CEA was so far only described to be pro-tumorigenic in an autocrine manner by inducing anti-apoptosis. Any potential paracrine effects of soluble CEA affecting tumor microenvironment including angiogenesis have not been described.
Here, we report that CEA released by tumor cells induced angiogenesis by directly inducing pro-angiogenic endothelial cells behavior. As shown by gain and loss of function in vivo tumor transplant models, CEA directly stimulated endothelial cell proliferation and migration in vitro and endothelial cell invasion and functional active capillary-tube formation in directed in vivo angiogenesis assays. Thereby, CEA activated endothelial cells via integrin beta-3, leading to FAK phosphorylation and c-src activation as well as induction of MEK/ERK- and PI3kinase/Akt- pathways. Interfering with this chain of events at different steps, such as downregulation of its putative receptor for CEA (CEAR) by shRNA bearing lentivirus or blockage of integrin activity, abrogated CEA-induced endothelial cell activation and tumor-angiogenesis leading to tumor growth arrest. Notably, CEA acted independently and partially additive to the VEGF / VEGFR-2 (KDR or flk-1) system. The biological relevance was further verified by analysis of paraffin-embedded tumor-tissue samples derived from colon cancer patients, whereas vascularization of the tumor microenvironment was significantly higher whenever CEA plasma levels were high.
Thus, our data indicate that the tumor marker CEA acts as a novel angiogenic molecule and might offer a potential therapeutic target in the treatment of tumor-angiogenesis.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B6.
Citation Format: Gerald W. Prager, Kira Braemswig, Marina Poettler, Christoph Zieleinski. CEA affects tumor- angiogenesis via integrin-dependent activation of endothelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B6.
Abstract B7: Angiopoietin like 7, a novel pro-angiogenetic factor over-expressed in cancer.
Authors: Parri Matteo , Pietrovito Laura , Grandi Alberto , campagnoli susanna , Pileri Piero , De Camilli Elisa , Bianchini Laura , Grandi Guido , Viale Giuseppe , Chiarugi Paola , Grifantini Renata Maria 
Published: August 2014

Abstract
Angiopoietin like (ANGPTL) proteins are secreted proteins showing structural similarity to members of the angiopoietin family. Some ANGPTL proteins possess pleiotropic activities, being involved in cancer lipid, glucose energy metabolisms and angiogenesis. ANGPTL7 is the less characterized member of the family whose functional role is only marginally known. In this study we provide experimental evidences that ANGPTL7 is over-expressed in different human cancers. To understand the role played by ANGPTL7 in tumor biology, we asked whether ANGPTL7 is endogenously expressed by malignant cells or in response to environmental stimuli. We found that ANGPTL7 is marginally expressed under standard growth condition while it is specifically up-regulated by hypoxia. The regulatory mechanism underlining the ANGPTL7 response to hypoxia need to be elucidated. Interestingly, the protein is secreted and partially associated with the exosomial fraction, suggesting that it could be found in the systemic circulation of oncologic patients and act in an endocrine way. Moreover we found that ANGPTL7 exerts a pro-angiogenetic effect on human differentiated endothelial cells by stimulating their motility, invasiveness and capability to form capillary-like networks while it does not stimulate bone marrow derived progenitor endothelial cells. Finally, we showed that ANGPTL7 promotes vascularization in vivo in the mouse matrigel sponge assay, thereby accrediting this molecule as a pro-angiogenic factor. This suggests that ANGPTL7 could be an attractive therapeutic target for anti-angiogenic tumor therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B7.
Citation Format: Matteo Parri, Laura Pietrovito, Alberto Grandi, susanna campagnoli, Piero Pileri, Elisa De Camilli, Laura Bianchini, Guido Grandi, Giuseppe Viale, Paola Chiarugi, Renata Maria Grifantini. Angiopoietin like 7, a novel pro-angiogenetic factor over-expressed in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B7.
Abstract B83: Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma.
Authors: Shi Wenyin , Lawrence Yaacov R. , Werner-Wasik Maria , Andrews David , Bar Ad Voichita , Evans James , Moshel Yaron , Farrell Christopher , Judy Kevin , Glass Jon , Kim Lyndon , Dicker Adam P. 
Published: August 2014

Abstract
Introduction: Panobinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitivity effect. This is an interim report of the phase I study to evaluate the safety and tolerability of panobinostat combined with fractionated stereotactic radiation therapy (FSRT) for patients with recurrent glioma.
Methods: This is a phase I trial with 3+3 design. Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was 30-35 Gy delivered in 10 daily fractions. Panobionostat was administrated by mouth, once daily, every Monday, Wednesday, and Friday with radiation treatment. Panobionostat was escalated from 10 to 30 mg.
Results: Fifteen patients were enrolled in the trial. Four patients were excluded from the analysis. One patient had tumor progression prior to initiation of treatment, and didn't receive panobinostat. Three patients didn't finish protocol treatment due to increase in QTc exceeding the protocol limit due to panobinostat toxicity. There was no treatment related grade 3 or higher toxicities in the 10 mg and 20 mg dose levels. Four patients were enrolled in the final dose level, 30 mg. One developed grade 3 leukopenia, and grade 4 low ANC (absolute neutrophil count). The hematological toxicities were possibly related to the treatment. Two more patients are required to compete the final dose level and determine the maximum tolerated dose of panobionostat when combined with FSRT in patients with recurrent glioma. Median follow up for living patient is six months. Median progression free survival, and overall survival have not been reached.
Conclusions: Panobinostat administrated with FSRT is well tolerated to the dose of 20 mg. The tolerability of 30 mg dose level is still under evaluation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B83.
Citation Format: Wenyin Shi, Yaacov R. Lawrence, Maria Werner-Wasik, David Andrews, Voichita Bar Ad, James Evans, Yaron Moshel, Christopher Farrell, Kevin Judy, Jon Glass, Lyndon Kim, Adam P. Dicker. Phase I trial of panobinostat and fractionated stereotactic radiation therapy for recurrent glioma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B83.
Abstract B9: Tumor growth rate analysis enables cost efficient design of preclinical pharmacology studies.
Authors: Guo Sheng , Li Jun , Zhang Juan , Qian Wubin , Shi Qian 
Published: August 2014

Abstract
Xenograft models are widely used in the oncology drug discovery and development process. However, the lack of available information regarding the xenograft models, such as growth curves, standard of care treatment results, IHC analysis of biomarkers, as well as target gene expression, mutation, and amplification, hampers the selection of suitable models for accurate evaluation of therapeutic molecules. We have created XenoBase™ that combines public cell line profiling data with our own pharmacology data on &gt;180 xenograft models. A searching engine is also built in the database to search for models based on gene mutation, expression, amplification, as well as SOC information, types (orthotopic, subcutaneous, systemic) of the xenograft models. The XenoBase™ will enable informed decision in selecting the most relevant models for the development of targeted therapeutics.
Armed with hundreds of xenograft studies available in the XenoBase™, we analyzed the tumor growth rate of each study to compare the results with traditional T/C analysis. The T/C analysis is the current standard, and a T/C value less than 0.42 is widely accepted as an indication of efficacy in evaluating a test article. However, this T/C analysis is limited in using only the data points on one day, overlooking the fact that tumor growth curves are generated over a long period of time (months) and with many days of data collection. To take advantage of the tumor growth curves, we analyzed tumor growth rate utilizing every data point, and derived growth rate based on slopes. Our analysis with the XenoBase™ data indicated that the growth rate based approach is more powerful in evaluating test articles for efficacy compared to T/C analysis or area under the curve (AUC) analysis. If adopted by the industry, this approach may save hundreds of millions of dollars spent in excess number of animals and prolonged observations that may not be necessary.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B9.
Citation Format: Sheng Guo, Jun Li, Juan Zhang, Wubin Qian, Qian Shi. Tumor growth rate analysis enables cost efficient design of preclinical pharmacology studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B9.
Abstract B92: Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways.
Authors: Lightcap Eric S. , Garcia Khristofer , Blank Jonathan L. , Bouck David C. , Liu Xiaozhen J. , Hather Greg , Berger Allison , Cosmopoulos Katherine , Thomas Michael P. , Kuranda Mike , Pickard Michael D. , Liu Ray , Bandi Syamala , Smith Peter G. 
Published: August 2014

Abstract
MLN4924 is an investigational small molecule inhibitor of the Nedd8-activating enzyme (NAE) currently in Phase 1 clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standards of care, including other DNA damaging agents. We studied the interaction of MLN4924 with other DNA damaging agents in a panel of 4 cell lines and found that mitomycin C, cisplatin, carboplatin, cytarabine, ultraviolet radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in at least 1 cell line. Further testing in xenograft-bearing mice demonstrated synergy of MLN4924 with mitomycin C and with carboplatin, and additivity with gemcitabine. Based in part on this data, MLN4924 is currently being evaluated in a Phase 1b trial (NCT01862328) with 3 combination arms: MLN4924 + carboplatin and paclitaxel, MLN4924 + gemcitabine, and MLN4924 + docetaxel. To evaluate the mechanism of synergy between MLN4924 and mitomycin C, in vitro experiments with RNAi were performed. Depletion of genes within the ATR and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924, results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may be applied to additional combinations currently under clinical evaluation.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B92.
Citation Format: Eric S. Lightcap, Khristofer Garcia, Jonathan L. Blank, David C. Bouck, Xiaozhen J. Liu, Greg Hather, Allison Berger, Katherine Cosmopoulos, Michael P. Thomas, Mike Kuranda, Michael D. Pickard, Ray Liu, Syamala Bandi, Peter G. Smith. Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B92.