bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4906: The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma
Authors: Orillion Ashley R. , Shen Li , Adelaiye-Ogala Remi , Elbanna May , Chintala Sreenivasulu , Arisa Sreevani , Pili Roberto 
Published: July 2016

Abstract
Background: Recent advances in immunotherapy have highlighted the antitumor effects of immune checkpoint inhibition. Novel anti-PD-1/PD-L1 immunotherapies have been shown to effectively overcome tumor avoidance of immune surveillance in several tumor types including renal cell carcinoma. Our group has recently shown that the selective class I HDAC inhibitor entinostat is effective in suppressing regulatory T cells and enhancing immunotherapies in murine renal and prostate models, RENCA and Myc-Cap respectively. In this study we have evaluated the combination of entinostat with an anti-PD-1 antibody in the RENCA renal cell carcinoma model.
Methods: 32 BALB/c female mice were implanted with the syngenic, orthotopic, renal cell carcinoma mouse model, RENCA - luciferase tagged - at day -8. Treatment (8 mice /group) with anti-mouse-PD-1 (aPD-1; 10mg/kg twice a week, I.P.), entinostat (5mg/kg 5 days a week), or combination of the two was begun at day 1. Bioluminescence imaging was performed at days -1, 9 and 19 to assess the orthotopic tumor growth. End point tumor weights were taken to assess the effect of combination treatment.
Results: Analysis of tumor growth showed a reduction of bioluminescence across the three time points in the combination group as compared to the vehicle and single agent treatments. Additionally, end point analysis of tumor weights revealed an overall reduction in the size of the tumors in the entinostat/anti-mPD-1 combination group (88% inhibition) as compared to the vehicle (p = 0.0002), aPD-1 alone (25% inhibition)(p = 0.0181), and entinostat alone (63% inhibition)(p = 0.0481) groups. Examination of the status of the infiltrating immune cells of the tumor microenvironment via flow cytometry, qRT-PCR, immunohistochemistry, and/or immunofluorescence analysis is ongoing.
Conclusions: Our preliminary results suggest that the immunomodulatory activity of the selective class I HDAC inhibitor entinostat may enhance the antitumor effect of PD-1/PD-L1 inhibition and provide the rationale for the clinical testing of this novel combination in patients with RCC.
Citation Format: Ashley R. Orillion, Li Shen, Remi Adelaiye-Ogala, May Elbanna, Sreenivasulu Chintala, Sreevani Arisa, Roberto Pili. The selective class I HDAC inhibitor entinostat enhances the antitumor effect of PD-1 inhibition in a syngeneic orthotopic murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4906.
Abstract 4911: SOCS-1 inhibits tumor growth by enhancing T cell mediated antitumor immunity related to PD-L1
Authors: Nakagawa Satoshi , Serada Satoshi , Matsuzaki Satoko , Ueda Yutaka , Yoshino Kiyoshi , Fujimoto Minoru , Kimura Tadashi , Naka Tetsuji 
Published: July 2016

Abstract
[Background]
In many solid cancers, constitutive activation of JAK/ signal transducers and activators of transcription (STAT) signaling pathway is associated with poor prognosis. Constitutive JAK/STAT signaling enhances the expression of cyclins and anti-apoptosis proteins, leads to the increased tumor cell proliferation and survival. Furthermore, one of the immune checkpoint molecules programmed cell death 1 ligand 1 (PD-L1), which is involved in the suppression of T cell mediated antitumor immunity, is induced by STATs. Suppressor of cytokine signaling (SOCS)-1 is a negative feedback molecule, which is induced by JAK/STAT signaling and inhibits the JAK activity, resulted in the suppression of JAK/STAT signaling. This study aimed to reveal the antitumor effects by SOCS-1 in vitro and in vivo.
[METHODS]
Five human OC cell lines (OVCAR-3, SKOV-3, RMG-1, A2780, ES-2) and 4 murine cancer cell lines (B16F10, LLC, 4T1, CT26) were assessed. SOCS-1 or LacZ were overexpressed by adenoviral vector. Anti-proliferative effect was assessed by WST-8 assay. Female BALB/c mice were injected with CT26 for subcutaneous xenograft experiments. AdSOCS-1 or AdLacZ was intra-tumorally administered every other day and PD-L1 expression in tumor cells and activation levels of tumor infiltrated T cells were analyzed by flow cytometry.
[RESULT]
Overexpression of SOCS-1 inhibited proliferation of all cancer cell lines. Three OC (OVCAR-3, SKOV-3, ES2) and all murine cancer constitutively expressed PD-L1. Expression levels of PD-L1 in OVCAR-3 and CT26 cells were downregulated about 30% compared with control by overexpressed SOCS-1 in vitro. In CT26 allografted model, SOCS-1 treatment significantly inhibited tumor growth (62.2±5.2%, P&lt;0.01)and suppressed expression of PD-L1 on CT26 cells in the tumor (65.2±8.4%, P&lt;0.05). Granzyme B and CD107a expression of intratumorally infiltrated CD8 T cells were increased more than 50% (P&lt;0.05) in the AdSOCS-1 injected group compared with AdLacZ injected group. PD-L1 Fc fusion protein significantly inhibited antitumor effect of SOCS-1.
[Conclusion]
SOCS-1 mediated inhibition of JAK/STAT signaling shows not only direct antitumor effect against tumor cells but also enhances T cell mediated anti-tumor immunity in vivo by downregulating the expression of PD-L1 on tumor cells and preventing the interaction of PD-1/ PD-L1.
Citation Format: Satoshi Nakagawa, Satoshi Serada, Satoko Matsuzaki, Yutaka Ueda, Kiyoshi Yoshino, Minoru Fujimoto, Tadashi Kimura, Tetsuji Naka. SOCS-1 inhibits tumor growth by enhancing T cell mediated antitumor immunity related to PD-L1. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4911.
Abstract 4937: Atm expression predicts ABT-888 and CPT-11 sensitivity in gastric cancer cells by mediating p53 independent regulation of cell cycle and apoptosis
Authors: Vijayasubhash Vinod , Tan Shihui , Yan Fui Leng , Liem Natalia , Yong Wei Peng 
Published: July 2016

Abstract
Background: Identification of synthetically lethal cellular targets and synergistic drug combinations are important in cancer chemo therapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signalling and cell cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its potential implication as a predictive biomarker for cancer chemotherapy remains unexplored. The present study evaluated ATM induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, ABT-888 and CPT-11 respectively.
Methods: ATM expression in a panel of 10 gastric cancer cells were detected by immunohistochemistry and the IC50 against ABT-888 and CPT-11 was determined by MTS cell proliferation assay. The synergistic effect of ABT-888 and CPT-11 in gastric cancer cells was determined by cell cycle and DNA damage assays. ATM expression was knocked down using siRNA and its effect in P53 induced cell cycle regulation and apoptosis was determined by immunoblot analysis.
Results and Conclusion: ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy, however showed a higher synergistic effect towards ABT-888 and CPT-11 combinational therapy that predisposed cells to enhanced drug sensitivity. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell cycle progression and apoptosis in a P53 independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cell to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM dependent regulation of cellular processes.
Citation Format: Vinod Vijayasubhash, Shihui Tan, Fui Leng Yan, Natalia Liem, Wei Peng Yong. Atm expression predicts ABT-888 and CPT-11 sensitivity in gastric cancer cells by mediating p53 independent regulation of cell cycle and apoptosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4937.
Abstract 4952: Co-expression of pAKT and MYC is associated with aggressive disease in human prostate cancer
Authors: Pértega-Gomes Nelma , Tyekucheva Svitlana , Penney Kathryn , Zadra Giorgia , Mucci Lorelei A. , Loda Massimo 
Published: July 2016

Abstract
Introduction: AKT and MYC are amongst the most prevalent oncogenes in prostate cancer (PCa). MYC cooperates with activated AKT in pre-clinical, genetically engineered in vivo models accelerating disease progression and increasing resistance to therapy. However, the clinical relevance of phosphoAKT/MYC co-expression in human prostate tumors remains unknown.
Experimental Procedures: A prospective cohort (Physicians’ Health Study and Health Professionals Follow-up Study) of 578 men with PCa with a mean 13-year follow up was used. Protein expression of MYC and phosphoAKT (Serine 473) was characterized by immunohistochemistry on tissue microarrays. pAKT and MYC expression was analyzed using the Cri Vectra/InForm multispectral analysis platform. The InForm software package was trained to segment PCa regions only (i.e., no stromal regions were included in the analysis). We used quantile normalization to adjust for the potential batch effects of protein expression staining across each of the tissue microarrays using the limma package R. The continuous score for pAKT and MYC were divided into quartiles and assigned a value of 1, 2, 3 or 4 for low (1), moderate (2 or 3) and high staining (4). Spearman correlations between pAKT, MYC and the clinico-pathological data were calculated.
Results: High pAKT and High MYC were co-expressed in 10% of patients. (Quartile 4). Also 10% were negative or weakly positive for both pAKT and MYC (Quartile 1). Only 3% of the High pAKT patients had weak or no expression of MYC and 4% of High_MYC patients had Low pAKT expression. The majority of patients were distributed in the Quartiles 2 and 3 (73%). Importantly, only High pAKT and High pMYC co-expressors were associated with tumor stage (pT3 or pT4) (p = 0.03), high Gleason Score (p = 0.021) and presence of metastatic disease (p = 0.011). GEP analysis showed that the same patients exhibited up-regulation of genes involved in cell invasion/migration capacity and stromal remodeling.
Conclusions: Co-expression of AKT and MYC is associated poor clinical outcome in PCa patients. Gene expression profiling suggest that concomitant activation of AKT and MYC results in the activation of pathways associated with an invasive phenotype.
Citation Format: Nelma Pértega-Gomes, Svitlana Tyekucheva, Kathryn Penney, Giorgia Zadra, Lorelei A. Mucci, Massimo Loda. Co-expression of pAKT and MYC is associated with aggressive disease in human prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4952.
Abstract 4977: Immunogenic chemotherapy synergize PD-1 blockade by enhancing dendritic cells infiltration in triple-negative breast cancer (TNBC)
Authors: Yuan Xiangliang , Xiao Yi , Kuo Wenling , Yu Dihua 
Published: July 2016

Abstract
Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) has achieved noteworthy benefit in multiple cancers. However, their efficacy remains unsatisfactory in triple-negative breast cancer (TNBC). Breast cancer is not highly mutagenic and immune checkpoints blockade therapies for TNBC is not as effective as for melanoma or lung cancer with high mutation rates. Combination of different modalities offers an opportunity to enhance their effect. We studied the synergistic effect of cancer chemotherapy and immunotherapy in TNBC mouse model. Here we report that the combination of Doxisome (liposomal encapsulated formulation of Doxorubicin) and anti-PD-1 antibody suppresses tumor growth, reduces lung metastasis and improves survival of mice bearing 4T1-triple negative breast cancer. Moreover, the combination of Doxisome and anti-PD-1 was able to overcome low dose Doxisome resistance in mouse models of TNBC. The success of anticancer chemotherapy is linked to a durable immune response of targeting tumor. We present evidence that the synergistic therapeutic activity of Doxisome with anti-PD1 blockade results in enhanced T cell anti-tumor immune responses. Moreover, the synergetic effect is due to increased dendritic cells (DCs) infiltration in tumor microenvironment, which internalize tumor antigens and subsequently activate tumor-reactive T cells. In TNBC mouse model, by combining anti-PD1 checkpoint blockade while shifting the immune response towards CD4+ Th1 with Doxisome, immune tolerance to TNBC tumor can be overcome. Enhancing antigen presenting cells (APCs, e.g. DCs) infiltration by immunogenic chemotherapy and T cell activation by anti-PD1 blockade increase therapy response in TNBC. These results provide rationale for several newly planned clinical trials combining immunogenic chemotherapy with PD-1 or PD-L1 blockade in breast cancer and exploration of such a combination in others solid tumors.
Citation Format: Xiangliang Yuan, Yi Xiao, Wenling Kuo, Dihua Yu. Immunogenic chemotherapy synergize PD-1 blockade by enhancing dendritic cells infiltration in triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4977.
Abstract 501: PD-L1 expressing circulating tumor cells (CTCs) in patients with breast cancer
Authors: Zavridou Martha , Strati Areti , Malamos Nikos , Georgoulias Vasilis , Lianidou Evi S. 
Published: July 2016

Abstract
Background: Programmed cell Death receptor Ligand 1 (PD-L1) is a very promising biomarker for the selection of patients for cancer immunotherapy. We recently developed a highly sensitive, specific and robust RT-qPCR assay for PD-L1 mRNA. The aim of the present study was to study the expression of PD-L1 in CTCs from breast cancer patients with verified metastasis.
Methods: We quantified the expression of PD-L1 mRNA transcripts in EpCAM-positive CTCs, by using our recently developed RT-qPCR assay, based on the following procedure: i) immunomagnetic enrichment of EpCAM-positive CTCs from 20mL of peripheral blood, ii) total RNA isolation iii) cDNA synthesis and iv) RT-qPCR for PD-L1. PD-L1 expression in respect to the expression of B2M as a reference gene, was normalized using the 2-ΔΔCt approach. Peripheral blood samples (20mL) were obtained from 22 breast cancer patients with verified metastasis and 14 healthy donors.
Results: According to our results, 11/22 (50%) of metastasis-verified breast cancer patients were found to be positive for PD-L1 overexpression in CTCs. These are preliminary results and these percentages may change, since the number of samples that we are analyzing is continuously increasing. Our results are in concordance with a recent study by Mazel et al (Mol Oncol 2015), that by using the CellSearch(®) system found PD-L1((+)) CTCs in 11/16(68.8%) patients with metastatic breast cancer.
Conclusion: This is the first time that a quantitative RT-qPCR molecular assay is used for the evaluation of PD-L1expression levels in EpCAM-positive CTCs in metastatic breast cancer patients. The assay is closed-tube, quantitative, highly specific and sensitive, and high-throughput. We are currently evaluating the assay in a large number of clinical samples.
Citation Format: Martha Zavridou, Areti Strati, Nikos Malamos, Vasilis Georgoulias, Evi S. Lianidou. PD-L1 expressing circulating tumor cells (CTCs) in patients with breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 501.
Abstract 5058: Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer
Authors: Paez Alejandra V. , Pallavicini Carla , Schuster Federico , Giudice Jimena , Valacco Pia , Labanca Estefania , Anselmino Nicolas , Ortiz Emiliano , Binaghi Maria , Cotignola Javier , Marti Marcelo , Bruno Luciana , Levi Valeria , Navone Nora , Vazquez Elba , Gueron Geraldine 
Published: July 2016

Abstract
Prostate Cancer (PCa) is the second leading cause of cancer in men. PCa cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize other organs. We have previously shown that heme-oxygenase 1 (HO-1) has a strong anti-tumoral effect in prostate cancer (PCa) and regulates the adhesive properties of PCa cells. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification and treatment. Towards this end, we undertook an in-depth mass spectrometry-based proteomics study to build the Heme-oxygenase 1 (HO-1) interactome in PCa, in an effort to identify HO-1 molecular partners associated to the integrity of the cellular architecture and assess actin dynamics of PCa cells under HO-1 modulation.
The proteomics analysis of HO-1 interacting proteins yielded several cytoskeletal-associated proteins regulating actin filament dynamics, such as gelsolin, lasp1, SIPA1L1, testin, moesin, tropomodulin and vinculin. The bioinformatics screening across the Oncomine platform revealed that the RNA expression profiles of the cytoskeletal HO-1 interacting proteins, lie within the 10 percent of the most consistently low-expressed genes in prostate adenocarcinoma compared to normal tissue.
Motility changes were assessed on fiber-like 2D migration scenarios displaying a reduced frequency in migration events and in migration speed under hemin exposure, a specific pharmacological inducer of HO-1. A significant higher proportion of filopodia-like protrusions among neighboring cells and cellular contacts were observed when HO-1 was induced; effects reversed under HO-1 silencing. Altogether, our experimental findings demonstrate that HO-1 modulation in PCa induces the remodeling of the actin filament architecture at filopodia, alters the migratory patterns and cellular morphology, showcasing the relevance of the cytoskeletal proteins as potential therapeutic targets against the aggressive and metastatic disease.
Citation Format: Alejandra V. Paez, Carla Pallavicini, Federico Schuster, Jimena Giudice, Pia Valacco, Estefania Labanca, Nicolas Anselmino, Emiliano Ortiz, Maria Binaghi, Javier Cotignola, Marcelo Marti, Luciana Bruno, Valeria Levi, Nora Navone, Elba Vazquez, Geraldine Gueron. Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5058.
Abstract 5061: Evaluating the role of durotactic migration in the tumor microenvironment
Authors: DuChez Brian J. , Yamada Kenneth M. 
Published: July 2016

Abstract
Durotaxis is a mechanism of directional migration in which cells respond to a stiffness gradient in their local microenvironment. While durotaxis has been characterized primarily in cells of mesenchymal origin, its role in cancer biology has not been clearly defined. At a cellular and molecular level, evidence suggests cancer cells sense and respond to the stiffening tumor microenvironment in a manner that promotes malignant and invasive characteristics. Given the gradual stiffening of tumors, it is interesting to speculate how durotaxis might contribute to cell flux to and from primary tumors and metastatic sites. We hypothesize that a durotactic mechanism may, in part, contribute to the dissemination of cancer cells into the stiffened microenvironment associated with primary tumors and also possibly with pre-metastatic sites.
To directly characterize the impact of local stiffness on directional migration, cancer cells were cultured on a hydrogel possessing a stiffness gradient, then imaged by time-lapse microscopy and tracked using custom automated tracking software. Automated cell tracking allows for unbiased, accurate, and high-speed generation of large migratory datasets not feasible with conventional manual tracking and enables more robust analysis of cell populations. Preliminary data reveal that multiple cancer cell lines respond to a stiffness gradient with directed migration towards the stiffer part of the gel. The strength of the directional migratory response to stiffness gradients was found to depend on the magnitude of stiffness a cell encounters. By manipulating stiffness gradients to accurately reflect stiffness encountered by cancer subtypes, we will better understand if a durotactic mechanism has a global or cancer-specific impact on disease progression.
Citation Format: Brian J. DuChez, Kenneth M. Yamada. Evaluating the role of durotactic migration in the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5061.