bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2821: GRK6 deficiency promotes tumor aggressiveness and metastasis in a murine model of human lung cancer .
Authors: Sutton Natalie , Smith Nikia , Thomas Ariel J. , Raghuwanshi Sandeep K. , Richardson Ricardo M. 
Published: August 2014

Abstract
G protein coupled receptor kinases (GRKs) phosphorylate the activated form of G protein coupled receptors (GPCRs) followed by the association of β-arrestin (βarr) with the phosphorylated receptor, desensitization and down-regulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis and wound healing. In this study, we sought to investigate the role of GRK6 in CXCR2-mediated tumorigenesis using a murine model of human lung cancer. Mice deficient in GRK6 (GRK6−/−) exhibited a significant increase in Lewis lung cancer (LLC) growth and metastasis relative to control littermates (GRK6+/+). GRK6 deletion had no effect on the expression of pro-angiogenic chemokine or vascular endothelial growth factor (VEGF), but up-regulated matrix metalloproteinase (MMP)-2 and MMP-9 release, tumor-infiltrating PMNs and microvessel density. Treatment of the mice with a CXCR2 inhibitor (SB225002) or a murine anti-CXCR2 antibody blocked the effect of GRK6 deletion. Surprisingly, a GRK6−/−/βarr2−/− double knockout animal model exhibited faster tumor growth relative to GRK6−/− or βarr2−/− animals. Exposure of GRK6−/−/βarr2−/− mice to the anti-CXCR2 antibody totally inhibited tumor growth. This suggest that the effects of βarr2 and GRK6 knockdown in CXCR2-mediated tumor development are additive. Altogether, the results indicate that CXCR2 couples to GRK6 to regulate angiogenesis, tumor progression and metastasis. Deletion of GRK6 increases the activity of the host CXCR2, resulting in greater PMN infiltration and MMP release in the tumor microenvironment thereby promoting angiogenesis and metastasis. Since GRK6−/−/βarr2−/− mice showed greater tumor growth relative to GRK6−/− or βarr2−/− mice, the data also suggest that CXCR2 couples to a different mechanism to mediate tumor progression and metastasis.
Citation Format: Natalie Sutton, Nikia Smith, Ariel J. Thomas, Sandeep K. Raghuwanshi, Ricardo M. Richardson. GRK6 deficiency promotes tumor aggressiveness and metastasis in a murine model of human lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2013-2821
Abstract 2827: A platform to study metastatic cancer.
Authors: Wong Andrew D. , Searson Peter C. 
Published: August 2014

Abstract
Metastasis is responsible for over 90% of cancer related deaths. While significant advances in visualizing metastasis have been made in vivo, the details of the biological and physical processes that govern invasion and intravasation remain poorly understood. The difficulty in studying metastasis stems from the complexity of the interface where invasion and intravasation take place, between the tumor's local tissue microenvironment and the vascular system. To elucidate the mechanistic events taking place during invasion and intravasation, we have developed a platform that positions tumor cells adjacent to an artificial vessel embedded in an extracellular matrix (ECM). Using live-cell, fluorescence microscopy, we study the complex interplay between highly metastatic cancer cells and a functional artificial microvessel lined with endothelial cells during tumor migration and intravasation. We hypothesize that an engineered platform that recapitulates the interactions between a tumor and a physiologically relevant artificial vessel within an extracellular matrix will allow the systematic study of the physical and biological properties that regulate invasion and intravasastion. Since there remain many gaps in our understanding of the biology and physics of invasion and intravasation, further insight into these poorly understood processes may provide new strategies to prevent the spread of cancer and reduce the high mortality rates associated with metastasis.
Citation Format: Andrew D. Wong, Peter C. Searson. A platform to study metastatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2013-2827
Abstract 283: Cancer MET at the metastatic lesion preserves the malignant features acquired via EMT.
Authors: Kudo-Saito Chie , Kawakami Yutaka 
Published: August 2014

Abstract
Purpose: Cancer EMT is one of the mechanisms to acquire malignant features including invasiveness, drug resistance and stemness. However, the subsequent mechanism after EMT toward progression has not been fully understood yet. Based on the EMT-centered theory, it is simply thought that the reversal event of EMT, “MET," is caused in the tumor cells at the distant metastatic lesions. However, the molecular mechanism still remains unclear. In this study, we attempted to clarify the “post-EMT” mechanism in tumor cells.
Results: Firstly, we prepared tumor cells harvested from metastatic lesions of mice after tumor implantation provisionally as “post-EMT” tumor cells. Murine metastatic melanoma B16-F10 cells were transduced with a neo resistant gene, and were subcutaneously (s.c.) implanted in many C57BL/6 mice to obtain spontaneous tumor metastasis. Three weeks later, various tissues including bone marrow were harvested from the mice, and the single-cell suspensions were cultured in G418-supplemented medium for tumor selection. To characterize the post-EMT tumor cells, RT-PCR, immunostaining and cellular functional assay were conducted. As compared to the primary tumor cells harvested from s.c. tumor tissues, these tumor cells proliferated extremely slowly, and were resistant to chemotherapeutics, but rapidly grew in vivo after implantation. However, these tumor cells were very adhesive accompanied by increase of epithelial markers such as E-cadherin, but not mesenchymal markers such as Snail, indicating epithelial features. In addition, its chemoresistance and in vivo tumorgenesis activity of these tumor cells were superior to those of even Snail-transduced B16-F10 tumor cells, which were harvested from the metastatic lesions in a similar way. DNA microarray analysis revealed the significant upregulation of epithelial markers and drug resistant genes such as c-kit and GDF15 in the post-EMT tumor cells, as compared to those of the Snail transfectant. These imply that “MET” may not be just a reversion of EMT.
Conclusions: These results suggest that tumor cells revert into an epithelial state preserving malignant features acquired via EMT even after Snail lost at the metastatic lesions toward progression. We are now attempting to elucidate the molecular mechanism specific for the unique transition utilizing DNA microarray data.
Citation Format: Chie Kudo-Saito, Yutaka Kawakami. Cancer MET at the metastatic lesion preserves the malignant features acquired via EMT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 283. doi:10.1158/1538-7445.AM2013-283
Abstract 2840: Dendritic cell-based immunotherapy targeting WT1 and MUC1 for advanced biliary tract cancer.
Authors: Kobayashi Masanori , Sakabe Tomoyo , Tanii Mitsugu , Abe Hirofumi , Takahashi Hedenori , Tsujitani Shun-ichi , Shimodaira Shigetaka , Yonemitsu Yoshikazu , Okamoto Masato , Nagaya Masaki 
Published: August 2014

Abstract
Objectives:Despite intensive chemotherapy for biliary tract cancer (BTC), the outcome is not enough. Dendritic cells are the powerful antigen-presenting cells that have attracted attention from the efficacy of DC-based immunotherapy against many types of cancers. The objective of this study was to clarify the safety and efficacy of dendritic cell therapy for BTC.Methods: This retrospective study selected patients who underwent DC-based vaccine for BTC between May of 2009 and February of 2012. The safety of this treatment, median survival time (MST), 1-year survival rate, objective response rate (ORR), and disease control rate (DCR) were evaluated. The univariate and multivariate analyses were performed to identify the efficacy of DC by a Cox proportional hazards analysis.Results:Twenty-seven patients were selected for the study. The patients, and all but one patient had previous therapy, 13 patients had undergone prior surgical resection, and 21 patients went on to receive chemotherapy. No serious treatment-related adverse events were observed during the study period. One-year survival rate from 1st vaccination was 22 % and from the initial diagnosis was 67%. The MST from 1st vaccination and from the initial diagnosis were 8.2 months and 18.5 months, respectively. DCR and ORR were 37% and 11%,respectively. None of 27 patients showed complete response (CR), but we have found out 3 cases of partial responses (PR) and 7 cases of stable disease (SD).Furthermore, LDH, CRP, DTH, Performance Status (PS), combination with lymphokine-activated killer, chemotherapy were found to be statistically significant independent risk factors in multivariate analysis.Conclusion: DC-based immunotherapy for BTC was safe and prolonged the MST of the patients with BTC compared to chemotherapy alone,comparing the result from UK ABC-02 trial. DC-based immunotherapy for BTC may another option for BTC patient who has no chance for curative surgery.
Citation Format: Masanori Kobayashi, Tomoyo Sakabe, Mitsugu Tanii, Hirofumi Abe, Hedenori Takahashi, Shun-ichi Tsujitani, Shigetaka Shimodaira, Yoshikazu Yonemitsu, Masato Okamoto, Masaki Nagaya. Dendritic cell-based immunotherapy targeting WT1 and MUC1 for advanced biliary tract cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2840. doi:10.1158/1538-7445.AM2013-2840
Abstract 2843: Recombinant Vaccinia virus expressing CD40L: a multipotent antitumor immunogenic reagent.
Authors: Panopoulos Evangelos , Trella Emanuele , Raafat Nermin , Mengus Chantal , Spagnoli Giulio , Zajac Paul 
Published: August 2014

Abstract
Recombinant vaccinia virus (rVV) is one of the most immunogenic viral vectors. Its immunogenicity can be further modulated by the insertion of transgenes or deletion of viral genes which are involved in immune responses or specific cellular pathways. We generated a rVV encoding human CD154 (CD40L) and confirmed an efficient licensing of antigen presenting cells (APC), upon infection with a non-replicating (psoralen UV-inactivated) CD40L-rVV, as demonstrated by increased expression of (i) surface ligand/receptors (MHC I/II, CD80), (ii) Th1 cytokines (IL-12, IL-15, TNFa) and most importantly (iii) an increased capacity to stimulate TAA specific CTL proliferation. The hereby presented results are further characterizing some aspects of the pleiotropic roles in immuno-oncology of CD40 triggering via CD40L expressing recombinant vaccinia virus.
One of the immuno-modulatory functions of CD40L-CD40 is to play a key role during CD8+ priming for the generation of memory responses. Using sorted naive CD8+ Tcells (CD45RA+CD62L+) primed with allogeneic CD14+ infected with rVV 40L we observed an increased central memory phenotype (CD45RO+ CD62L+) as compared to culture primed with wild type virus infected cells. Moreover, rVV-CD40L stimulation of CD14+ cells also led to the inhibition of co-cultured tumor cells’ proliferation, correlating with increased TNFα expression. Finally, apoptosis of CD40+ tumor cell lines was induced upon direct infection with this CD40L non-replicating recombinant virus.
These data are confirming the potent capacities of recombinant vaccinia viruses expressing CD40L to efficiently trigger multiple CD40 mediated anti-tumor pathways. Not only this vector enhances the generation of tumor specific CD8+ T cells effector and memory responses, but it also promotes anti-tumoral functions of innate immune cells and is even able to directly induce apoptosis in CD40+ tumor cells. These in-vitro observations underline the strong clinical potential of recombinant vaccinia virus expressing CD40L in cancer viro- and immunotherapies.
Citation Format: Evangelos Panopoulos, Emanuele Trella, Nermin Raafat, Chantal Mengus, Giulio Spagnoli, Paul Zajac. Recombinant Vaccinia virus expressing CD40L: a multipotent antitumor immunogenic reagent. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2843. doi:10.1158/1538-7445.AM2013-2843
Abstract 2846: Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma .
Authors: Gavazza Alessandra , Lubas George , Fridman Arthur , Peruzzi Daniela , Impellizeri Joseph A. , Luberto Laura , Marra Emanuele , Roscilli Giuseppe , Ciliberto Gennaro , Aurisicchio Luigi 
Published: August 2014

Abstract
Background: We have recently shown that a genetic vaccine targeting dog telomerase (dTERT) and based on Ad/DNA-EGT technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with COP chemotherapy regimen.
Objectives: Here, we have conducted a double arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response and evaluated potential toxic effects of the immunotherapy along with a follow up of patients survival for three years and half.
Methods: The immune response was measured by ELISPOT. The expression of dTERT was quantified by quantitative PCR. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment.
Results: dTERT-specific cell mediated immune responses were induced in almost all treated animals No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP treated dogs was significantly increased over the COP-only treated cohort (&gt;76.1 vs 29.3 weeks, respectively, p&lt;0.0001). There was a significant association between dTERT expression levels and overall survival (OS) among vaccinated patients. Conclusions and Clinical relevance: Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach in human trials and for other cancer types.
Citation Format: Alessandra Gavazza, George Lubas, Arthur Fridman, Daniela Peruzzi, Joseph A. Impellizeri, Laura Luberto, Emanuele Marra, Giuseppe Roscilli, Gennaro Ciliberto, Luigi Aurisicchio. Safety and efficacy of a genetic vaccine targeting telomerase plus chemotherapy for the therapy of canine B-cell lymphoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2846. doi:10.1158/1538-7445.AM2013-2846
Abstract 2847: Molecular determinants of sensitivity and resistance to tumor-directed antibody-dependent cellular cytotoxicity (ADCC).
Authors: Murray Joseph C. , Nasto Rochelle E. , Jablonski Sandra A. , Tang Yong , Weiner Louis M. 
Published: August 2014

Abstract
Monoclonal antibodies can induce antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells, such as natural killer (NK) cells. Although clinical evidence suggests a role for ADCC in effective antibody therapy of cancer, molecular determinants of ADCC responsiveness—in oncogenic signaling networks, for example—have not been well characterized. Using an in vitro model system including an NK-like cell line (NK92-CD16V), cetuximab, and A431 cells, we screened 60 genes from an EGFR gene network by RNAi to assess for synthetic enhancement of ADCC. Primary and validation screens, and correlative characterization studies, identified four genes whose knockdown enhanced ADCC: GRB7, PRKCE, RET, and ABL1. Inhibition of Abl kinase activity enhanced ADCC, phenocopying the effects of ABL1 knockdown and providing pre-clinical evidence for combining Abl inhibitors and cetuximab. Next, we derived an ADCC-resistant cell population (A431/ADCC-R) by treating parental A431 cells with over 30 successive ADCC treatments. We describe the development, screening, and characterization of A431/ADCC-R. Our screening strategy has revealed molecular determinants of both tumor cell sensitivity and resistance to ADCC in vitro that may translate into increased monoclonal antibody efficacy in the clinic.
Citation Format: Joseph C. Murray, Rochelle E. Nasto, Sandra A. Jablonski, Yong Tang, Louis M. Weiner. Molecular determinants of sensitivity and resistance to tumor-directed antibody-dependent cellular cytotoxicity (ADCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2847. doi:10.1158/1538-7445.AM2013-2847
Abstract 2849: Pharmacodynamic biomarkers of anti-PD-L1 activity in pre-clinical mouse tumor models.
Authors: Boe Marigold , Huseni Mahrukh , Jiang Brittany , Koeppen Hartmut , Maecker Heather , Irving Bryan , Hegde Priti , Kowanetz Marcin 
Published: August 2014

Abstract
Programmed cell death 1 ligand 1 (PD-L1, CD274, B7-H1) is an immune checkpoint molecule expressed in various tissues, including multiple peripheral blood mononuclear cells and placenta. PD-L1 binds its receptor PD-1 on activated T cells to negatively regulate their function in both physiological and pathological conditions. PD-L1 also binds B7.1 (CD80), further down modulating immune responses. Importantly, numerous cancers resist T-cell mediated cytotoxic activity by over-expressing PD-L1.
The goal of this study was to identify pharmacodynamic biomarkers of response to agents blocking PD-L1/PD-1 pathway in pre-clinical models. CT-26 and MC-38 murine mouse tumor models were selected for this analysis, based on their PD-L1 expression and in-vivo sensitivity to anti-PD-L1 treatment. Tumors have been collected at various time points following treatment with an antibody blocking PD-L1 binding to PD-1 and B7.1. Subsequently, FACS, IHC, qPCR and a multiplex qPCR-based expression assay measuring a panel of ∼90 immune-related biomarkers have been used to evaluate changes in major immune cell subtypes and their activation status. We show that the intra-tumoral immune environment undergoes a time-sensitive dynamic modulation in response to PD-L1 pathway blockade, including an early and potent Th1 driven CTL response, as measured by relevant markers. Additionally, our findings show that targeting PD-L1 in pre-clinical tumor models can reinvigorate the host immune responses against the tumor and lead to T-cell mediated tumor killing. Our data also support identification of potential pharmacodynamic biomarkers that can be used to monitor activity of agents targeting the PD-L1 pathway in the clinic.
Citation Format: Marigold Boe, Mahrukh Huseni, Brittany Jiang, Hartmut Koeppen, Heather Maecker, Bryan Irving, Priti Hegde, Marcin Kowanetz. Pharmacodynamic biomarkers of anti-PD-L1 activity in pre-clinical mouse tumor models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2849. doi:10.1158/1538-7445.AM2013-2849
Abstract 2850: Predicting anti-tumor responses to phosphatidylserine targeting antibodies using tumor imaging.
Authors: Gong Jian , Archer Richard , Nguyen Van , Hughes Christopher C.W. , Hutchins Jeff , Freimark Bruce 
Published: August 2014

Abstract
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane and becomes exposed on tumor vascular endothelial cells and tumor cells in response to chemotherapy, irradiation and oxidative stresses in the tumor microenvironment. Binding of antibodies targeting PS on the tumor endothelial cells and tumors induces the recruitment of immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. Fully human antibody PGN635 binds PS through the interaction of beta-2-glycoprotein 1 (β2GP1) in the same manner as bavituximab. Using human PC-3 prostate tumor xenografts in SCID mice, we demonstrate that targeting of PS in tumors by PGN635 is enhanced by chemotherapy. Combination of PGN635 with docetaxel inhibited tumor growth compared to the control IgG plus docetaxel group (p&lt;0.05). Near-infrared optical imaging of PS in tumors with PGN650, an F(ab’)2 antibody fragment of PGN635, showed tumor growth inhibition in mice treated with docetaxel correlates with PS expression levels in the tumors. Maximal uptake of the PS imaging was observed when chemotherapy was given 24 hours before the imaging probe.
Citation Format: Jian Gong, Richard Archer, Van Nguyen, Christopher C.W. Hughes, Jeff Hutchins, Bruce Freimark. Predicting anti-tumor responses to phosphatidylserine targeting antibodies using tumor imaging. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2850. doi:10.1158/1538-7445.AM2013-2850