bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4213: Gene therapy for esophageal squamous cell carcinoma using SOCS-1 expressing adenoviral vector
Authors: Hara Hisashi , Nakatsuka Rie , Takahashi Tsuyoshi , Serada Satoshi , Fujimoto Minoru , Miyazaki Yasuhiro , Makino Tomoki , Kurokawa Yukinori , Yamasaki Makoto , Miyata Hiroshi , Nakajima Kiyokazu , Takiguchi Shuji , Mori Masaki , Doki Yuichiro , Naka Tetsuji 
Published: August 2015

Abstract
Objective Esophageal squamous cell carcinoma (ESCC) is the major histological form of oesophageal cancer in East Asian countries. Despite recent improvements in multimodality treatment, including surgery, radiotherapy and chemotherapy, the prognosis for patients with ESCC remains unsatisfactory. Therefore, development of novel therapy is urgently required. Suppressor of cytokine signaling-1 (SOCS-1) has been cloned as a negative regulator of various cytokine signaling. Recently, lines of evidences suggest that overexpression of SOCS-1 has been considered as a promising therapeutic approach for treatment of cancer. This study was aimed to evaluate the therapeutic effect of the overexpression of SOCS-1 by adenoviral vector (AdSOCS-1) against ESCC.
METHODS By WST-8 assay, cell growth inhibition via infection with various dose of AdSOCS-1 was evaluated in 11 ESCC cell lines in vitro. We also evaluated the induction of apoptosis by overexpression of SOCS-1 in vitro. To evaluate the therapeutic efficacy of AdSOCS-1, ESCC cell line (TE-8) was subcutaneously implanted into the ICR nu/nu mice. In addition, therapeutic efficacy was also assessed using human xenografts subcutaneously transplanted in imuune-deficient mice. Mice were intra-tumorally injection with AdSOCS-1 or control adenovirus vector (AdLacZ) twice a week for 4weeks.
RESULTS Among 11 ESCC cell lines, AdSOCS-1, markedly suppressed proliferation of 8 ESCC cell lines in vitro. AdSOCS-1 strongly induced apoptosis in vitro, via inhibiting JAK/STAT3 pathway. In the TE8 xenograft model, the volume of tumors after therapy in AdSOCS-1 group (1,580 ± 1,005mm3) were lower than that in control group (2,690 ± 1,309mm3). Furthermore, compared with AdLacZ, injection with AdSOCS-1 also inhibited the tumor growth of patient derived ESCC xenografts.
CONCLUSIONS Our results indicated that overexpression of SOCS-1 inhibited the progression of ESCC both in ESCC cell lines and ESCC xenograft model derived from patient. SOCS-1 can be a promising novel therapeutic approach for intra-lesional therapy in ESCC.
Citation Format: Hisashi Hara, Rie Nakatsuka, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Tetsuji Naka. Gene therapy for esophageal squamous cell carcinoma using SOCS-1 expressing adenoviral vector. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4213. doi:10.1158/1538-7445.AM2015-4213
Abstract 4219: Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells
Authors: Lai Yun-Ju , Tsai Jui-Cheng , Tseng Ying-Ting , Benveniste Etty N. 
Published: August 2015

Abstract
Glioblastoma is the most common and aggressive malignant primary brain tumor in adults. Its invasiveness and resistance to traditional therapies make it a highly recurrent malignant disease with poor prognosis. The existence of glioblastoma stem cells (GSC) may account for its invasiveness and high recurrence, so GSCs become a suitable target for developing new treatments. Rac proteins belong to the Rho small GTPase subfamily, which major functions include regulation of cell movement, proliferation, and survival. However, most of the studies focused on Rac1 but not other Rac family proteins. To investigate whether other Rac proteins, Rac2 and Rac3, can serve as new therapeutic targets for glioblastoma, especially for glioblastoma stem cells, we examined the effects of Rac1-3 on glioblastoma cells-derived tumorspheroids (glioblastoma stem-like cells). We found that Rac1-3 are important for cell proliferation and colony formation of glioblastoma stem-like cells. We also established the zebrafish xenotransplantation model to further study the effects of Rac proteins in glioblastoma, and observed that the cells expressing control scramble short-hairpin RNA sequence induced angiogenesis in the egg yolk of the fish, while the cells expressing siRacs shrank inside the fish and did not induce angiogenesis. The overall survival rates of fishes were also higher in the fishes injected with siRac cells instead of fishes with control scramble RNA cells. Furthermore, Rac proteins also involve in STAT3 and ERK activation, and regulate the GSC marker expression such as CD133, Sox2 and HIF-2α in glioblastoma stem-like cells. In conclusion, Rac proteins can serve as the potential therapeutic targets against glioblastoma and its stem cells.
Citation Format: Yun-Ju Lai, Jui-Cheng Tsai, Ying-Ting Tseng, Etty N. Benveniste. Small G protein Rac GTPases regulate the maintenance of glioblastoma stem-like cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4219. doi:10.1158/1538-7445.AM2015-4219
Abstract 4228: Identification of distinct mammary cancer stem cells with differential requirements for the autophagy regulator FIP200
Authors: Yeo Syn K. , Wen Jian , Chen Song , Guan Jun-Lin 
Published: August 2015

Abstract
Cancer stem cells (CSCs) contribute to intratumoral heterogeneity and have been implicated in disease relapse and drug resistance. Added to this complexity is the idea that distinct CSC populations can coexist within a tumor and hence, the understanding of this diversity is imperative for effective therapeutic targeting. In this study, we show the co-existence of distinct breast CSC populations which can be identified by ALDH+ and CD29+CD61+ markers respectively using the MMTV-PyMT driven mouse model of breast cancer. While both of these populations exhibit enhanced tumor initiating potential in Nude mice relative to bulk tumor cells, the CD29+CD61+ population have increased invasive abilities and display higher expression of epithelial to mesenchymal (EMT) associated genes. As autophagy has been associated with the acquisition of breast CSC traits, we went on to address the requirement for autophagy in ALDH+ and CD29+CD61+ populations through the deletion of the autophagy regulator, FIP200 in MMTV-PyMT driven tumors. Interestingly, FIP200 deletion only reduces the percentage of CD29+CD61+ cells but does not affect the percentage of ALDH+ cells. However, the tumor initiating properties of both ALDH+ and CD29+CD61+ cells were impaired upon FIP200 deletion. The decrease in the number and CSC potential of CD29+CD61+ cells correlated with diminished TGF-beta signalling upon FIP200 deletion as indicated by decreased TGF-b2, TGF-b3 and phospho-SMAD2 levels. FIP200 deletion also reduced STAT3 activation and it remains to be addressed whether this is responsible for decreased CSC potential in ALDH+ cells. Altogether, our results demonstrate the presence of distinct CSCs in MMTV-PyMT tumors with potentially distinct requirements for divergent signaling pathways. Importantly, we also show that the autophagy regulator FIP200 plays a crucial role in governing the CSC properties of these distinct CSC populations and could represent a potential therapeutic target against breast CSCs.
Citation Format: Syn K. Yeo, Jian Wen, Song Chen, Jun-Lin Guan. Identification of distinct mammary cancer stem cells with differential requirements for the autophagy regulator FIP200. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4228. doi:10.1158/1538-7445.AM2015-4228
Abstract 4276: Engineering a trivalent lupus anti-DNA autoantibody fragment for cancer therapy
Authors: Patel Jaymin M. , Noble Phil W. , Chan Grace , Weisbart Richard H. , Hansen James E. 
Published: August 2015

Abstract
Discovery and design of agents that selectively kill malignant cells but spare normal tissue is critical to the development of effective cancer therapies. 3E10 is a lupus anti-DNA autoantibody that penetrates cell nuclei, binds DNA and inhibits DNA repair in a manner that does not kill normal cells but is synthetically lethal to cancer cells with defective homology-directed repair of DNA double-strand breaks due to BRCA2-deficiency. To develop a more potent version of 3E10 for further testing in cancer therapy, we have engineered a trivalent fragment of 3E10 with mutations that enhance nuclear penetration and DNA binding. cDNA encoding a tandem trivalent single chain variable fragment of 3E10 (3E10 tri-scFv) with the D31N enhancing mutation in CDR1 of the heavy chain variable regions was designed and cloned into the pPICZαA yeast expression vector. 3E10 tri-scFv was expressed in and purified from Pichia pastoris. Biochemical characterization of 3E10 tri-scFv by SDS-PAGE and Western blotting confirmed purification of the expected protein product, and cell-penetration assays demonstrated increased efficacy of nuclear uptake by 3E10 tri-scFv. Clonogenic survival assays with BRCA2-deficient cancer cells similarly indicated enhanced synthetic lethality mediated by 3E10 tri-scFv. These findings indicate 3E10 tri-scFv is a promising candidate for further development as a targeted therapy for DNA repair-deficient malignancies and demonstrate the potential utility in engineering multivalent derivatives of other promising lupus autoantibodies intended for development as targeted cancer therapies.
Citation Format: Jaymin M. Patel, Phil W. Noble, Grace Chan, Richard H. Weisbart, James E. Hansen. Engineering a trivalent lupus anti-DNA autoantibody fragment for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4276. doi:10.1158/1538-7445.AM2015-4276
Abstract 4282: All-trans retinoic acid enhances the effector functions of the anti-CD38 antibody SAR650984
Authors: Bush Lucas , Harper David , Greco Rita , Song Zhili , Yang Guang , Adrian Francisco 
Published: August 2015

Abstract
SAR650984 is a humanized IgG1 monoclonal antibody selectively targeting CD38 that is in clinical development for the treatment of multiple myeloma (MM). SAR650984 eliminates MM cells through different mechanisms, including antibody dependent cytotoxicity and phagocytosis (ADCC and ADCP, respectively), complement dependent cytotoxicity (CDC), and direct induction of apoptosis. The aim of this study was to assess the cell killing activity of SAR650984 following genetic and chemical manipulation of CD38 expression in MM cells.
We established several MM cell lines engineered to overexpress CD38; median levels of CD38 were 537,000 receptors/cell, versus 29,000 receptors/cell in the parental cell lines. ADCC, ADCP, CDC, and apoptosis induced by SAR650984 treatment were all significantly increased in the CD38-overexpressing lines compared with the parental cell lines.
Based on these data, we hypothesized that pre-treatment of MM cells with all-trans retinoic acid (ATRA) would enhance the activity of SAR650984, since ATRA can induce up-regulation of CD38 expression. Treatment of the MM cell lines JJN-3, ARH-77, U266, Karpas-620, SKMM-2, RPMI-8226, NCI-H929, KMS-12PE and MOLP-8 with ATRA resulted in a dose-dependent 1.4- to 6.7-fold up-regulation of cell surface expressed CD38. Pretreatment of MM cells with ATRA for 48 hours resulted in enhanced SAR650984-mediated ADCC and ADCP compared to non-pretreated cells. The enhancement of ADCC and ADCP activity by ATRA pretreatment was recorded in all the cell lines tested.
In conclusion, these in vitro data are supportive of further evaluation of the combination of SAR650984 and ATRA for the treatment of MM.
Citation Format: Lucas Bush, David Harper, Rita Greco, Zhili Song, Guang Yang, Francisco Adrian. All-trans retinoic acid enhances the effector functions of the anti-CD38 antibody SAR650984. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4282. doi:10.1158/1538-7445.AM2015-4282
Abstract 430: MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways
Authors: Ibrahim Sherif A. , Elghonaimy Eslam A. , El-Shinawi Mohamed , El-Halawany Medhat , Nouh Mohamed A. , El-Mamlouk Tahani , Sloane Bonnie F. , Mohamed Mona Mostafa 
Published: August 2015

Abstract
Background
Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Recently, we have shown that macrophages isolated from the tumor microenvironment of IBC patients secrete monocyte chemoattractant protein-1/CC-chemokine ligand 2 (MCP-1/CCL2) and IL-8 that augment dissemination and metastasis of IB carcinoma cells. However, the precise molecular mechanism by which these cytokines exert their effect is still unclear.
Methods
In the present study, the triple negative breast cancer (TNBC) cell lines Sum149 (IBC) and HCC70 (non-IBC) cells were employed to analyze the effect of IL-8 and MCP-1/CCL2 on the proteolytic activity using live cell imaging assay, expression of cathepsin B and the activation status of STAT3, AKT, JAK1 and Src. In addition, we enrolled TNBC patients sub-grouped into IBC (n = 15), non-IBC (n = 19) patients.
Results
Our results revealed that upon stimulation with MCP-1/CCL2 and IL-8, Sum149 cells and HCC70 exhibited an increase in DQ-collagen degradation-mediated proteolytic activity. Mechanistically, MCP-1/CCL2 and IL-8 increase collagen degradation via enhanced expression of cathepsin B single chain mature enzyme (31 kDa) and the heavy chain of double chain mature enzyme (25/26 kDa). Moreover, MCP-1/CCL2 and IL-8 enhance activation of STAT3, ERK1/2 and AKT in both Sum149 and HCC70 cells. Interestingly, we detected over-expression of cathepsin B in the carcinoma tissues of TNBC-IBC patients compared to non-IBC patients. Over expression of cathepsin B found to be associated with activation of Src and ERK1/2, in IBC as compared to non-IBC tissues.
Conclusions
Our data indicate that MCP-1/CCL2 and IL-8 stimulate proteolytic activity, cathepsin B expression and Src-ERK1/2 pathway in IBC tissues versus non-IBC. Targeting MCP-1/CCL2 and IL-8 in triple negative IBC patients represents a promising therapeutic strategy.
Citation Format: Sherif A. Ibrahim, Eslam A. Elghonaimy, Mohamed El-Shinawi, Medhat El-Halawany, Mohamed A. Nouh, Tahani El-Mamlouk, Bonnie F. Sloane, Mona Mostafa Mohamed. MCP-1/CCL2 and IL-8 regulate proteolytic activity of triple negative inflammatory breast cancer via cathepsin B, ERK1/2, JAK1 and Src signaling pathways. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 430. doi:10.1158/1538-7445.AM2015-430
Abstract 4301: Endothelial angiopoietin-2 expression correlates with tumor angiogenesis and response to sunitinib in metastatic renal cell carcinoma
Authors: Lampinen Anita , Rautiola Juhana , Mirtti Tuomas , Ristimäki Ari , Joensuu Heikki , Bono Petri , Saharinen Pipsa 
Published: August 2015

Abstract
Background: Angiopoietin-2 (Ang2) is an endothelial cell derived growth factor, which promotes tumor angiogenesis, tumor growth and metastasis. Ang2 is a promising target for anti-angiogenic therapies, but its potential as a biomarker for anti-angiogenic therapies remains unknown. The purpose of this study was to evaluate expression of the Ang2-Tie2 signalling pathway components in metastatic RCC (mRCC) patients treated with sunitinib, a modern multitarget TKI.
Materials and methods: We evaluated Ang2, CD31 and Ki67 expression in tumors of 136 patients with metastatic RCC (mRCC) treated with first-line sunitinib from formalin-fixed paraffin-embedded tumor samples using immunohistochemistry.
Results: Ang2 was exclusively expressed in the endothelial cells of tumor blood vessels. Using a cutoff of ≥50 Ang2+ vessels/microscopic field, 38% of the samples had high Ang2 expression. High Ang2 expression correlated with high CD31+ vessel density (p = 0.002). 91% of patients with high Ang2 expression had partial response (PR) or stable disease (SD) as best response to sunitinib as compared with 76% of those with low Ang2 expression (P = 0.033). High CD31+ vessel density correlated with a high clinical benefit rate (P = 0.015), and with low levels of Ki-67+ tumor cells (P = 0.018). Combined high expression of both Ang2 and CD31 predicted even better clinical benefit rate with 100% of the patients with high Ang2 and CD31 expression (n = 25) achieving PR/SD as compared with 77% among the rest of the patients (n = 101; P = 0.007). Only one patient (8%, n = 12) with papillary RCC, but 49 (41%) patients with clear cell RCC had high Ang2 expression (P = 0.03).
Conclusions: In this first study to investigate Ang2 expression and outcome in mRCC patients treated with sunitinib, high Ang2 expression in the tumor vasculature was predictive for sunitinib efficacy.
Citation Format: Anita Lampinen, Juhana Rautiola, Tuomas Mirtti, Ari Ristimäki, Heikki Joensuu, Petri Bono, Pipsa Saharinen. Endothelial angiopoietin-2 expression correlates with tumor angiogenesis and response to sunitinib in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4301. doi:10.1158/1538-7445.AM2015-4301
Abstract 4304: MMP-9 as a marker of response to treatment with B-Raf inhibitors in cutaneous melanoma
Authors: Candido Saverio , Malaponte Grazia , Salemi Rossella , Pezzino Franca Maria , Scalisi Aurora , McCubrey James A. , Libra Massimo 
Published: August 2015

Abstract
Malignant melanoma is an aggressive tumor of the skin with a poor prognosis for patients with advanced disease. In melanoma, both the Ras/Raf/MEK/ERK (MAPK) and the PI3K/AKT (AKT) signaling pathways are constitutively activated through multiple mechanisms. Although, at present it has been demonstrated that the treatment with B-Raf enzyme inhibitors improve survival of melanoma patients, still these patients may relapse or become resistant to treatment. Therefore, there is a need to identify novel factors involved in melanoma development and/or progression.
Matrix metalloproteinases (MMP) have been regarded as critical molecules in promoting tumor cell metastasis. Prognostic and diagnostic significance of MMP-9 overexpression has been shown in several cancer types. However, their role in melanoma was not fully investigated. Thus, we hypothesized that MMP-9 overexpression in melanoma may be involved in transformation and act as a prognostic biomarker.
On this light, MMP-9 circulating levels, and MMP-9 gelatinase activity were measured by ELISA and zymography in a total of 148 melanoma samples with and without BRAFV600E mutation compared to healthy controls. The results showed that highest circulating levels of MMP-9 and MMP-9 activity were associated with advanced stages of disease. We have also demonstrated that higher levels of MMP-9 were detected among melanoma samples harboring BRAFV600E mutation compared to those BRAFWT.
We further investigated if MMP-9 may be associated with acquired resistance to B-Raf inhibitors, such as Dabrafenib. Functional in vitro experiments were performed using commercial available melanoma cell lines. The results showed that MMP-9 was down-regulated in melanoma cells after treatment with Dabrafenib. While, higher MMP-9 expression levels were observed in the resistant clones compared to those detected in the parental cells. Intriguingly, similar trend was observed for pERK expression.
Overall, these data indicate that MMP-9 may play a role for the evaluation of response to treatment with B-Raf inhibitors in melanoma patients.
Note: This abstract was not presented at the meeting.
Citation Format: Saverio Candido, Grazia Malaponte, Rossella Salemi, Franca Maria Pezzino, Aurora Scalisi, James A. McCubrey, Massimo Libra. MMP-9 as a marker of response to treatment with B-Raf inhibitors in cutaneous melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4304. doi:10.1158/1538-7445.AM2015-4304
Abstract 4307: In vitro drug sensitivity and genetic profile analysis from primary culture obtained from brain cancer
Authors: Kipper Franciele C. , Mendonça Louise C. , Becker Rafael , Confortin Gláucia , Ledur Pítia F. , Marc André , Paglioli-Neto Eliseu , Viola Fabiana , Morrone Fernanda B. , Lenz Guido 
Published: August 2015

Abstract
The Cancer Genome Atlas effort subtyped gliomas in four molecular groups based on gene expression, mutation and deletion and retrospectively linked these subtypes to chemotherapy response. But up to now there is no protocol to use this or other methods to predict chemotherapy response in the clinic for gliomas. Patients are normally treated with ratiotherapy and temozolomide (TMZ) in a protocol of 5 days of treatment and 23 days of recovery. The goal of this study is to analyze gene expression and drug sensitivity in a relevant time frame to prospectively contribute to therapeutic decisions. For this, we prepared 19 cell cultures from 19 biopsies of brain tumors and treated them with a range of chemotherapy agents (TMZ, carmustine, lomustine, cisplatin, etoposide, paclitaxel, irinotecan, procarbazin, mebendazol, vincristin and vinblastin) at plasmatic concentration. Cells were counted for at least 12 days after treatment or tested for viability after 7 or 14 days and more that 60% reduction was considered a positive response. From eleven cell cultures tested with viability assay, only one responded to temozolomide (the first line chemotherapy for this tumor) after a single administration. The strongest effect was obtained using anti-microtubule agents. Cell counting after 12 days of treatment confirmed the resistance to TMZ and the sensitivity to antimicrotubule drugs, particularly paclitaxel. Combination of procarbazin, lomustine and vincristine (PCV), previously used to treat glioblastoma patients, killed very effectively cells of only 1 patient. The cell cultures from three of five patients display EGFR over-expression and four of five presented p53 and p21 expression. At this time, we are not able to correlate gene expression, subtyping and drug sensitivity. From these data we conclude that brain tumors can be routinely grown and tested for drug sensitivity in a time frame that more closely mimics the treatment of patients.
Ethical protocol number UFRGS: 420.856; PUCRS: 429.849 Financial support: FAPERGS, CNPq e CAPES.
Citation Format: Franciele C. Kipper, Louise C. Mendonça, Rafael Becker, Gláucia Confortin, Pítia F. Ledur, André Marc, Eliseu Paglioli-Neto, Fabiana Viola, Fernanda B. Morrone, Guido Lenz. In vitro drug sensitivity and genetic profile analysis from primary culture obtained from brain cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4307. doi:10.1158/1538-7445.AM2015-4307