bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR 20th Anniversary Commentary: Setting the Stage for Nanoparticle Albumin-Bound Paclitaxel—How Far Science Has Come
Authors: Bashour Sami I. , Ibrahim Nuhad K. 
Published: May 2015

Abstract
In this phase I pharmacokinetic study of ABI-007, which was published in the May 1, 2002, issue of Clinical Cancer Research, Ibrahim and colleagues provided the framework needed for subsequent studies to confirm the benefits of ABI-007 over solvent-based formulations. Since the study's publication, experiments have highlighted the importance of drug-delivery systems, the immune system in cancer biology, and immunoregulatory properties of taxane compounds. Clin Cancer Res; 21(9); 1975–7. ©2015 AACR.
See related article by Ibrahim et al., Clin Cancer Res 2002;8(5) May 2002;1038–44
Targeting Notch Signaling with a Notch2/Notch3 Antagonist (Tarextumab) Inhibits Tumor Growth and Decreases Tumor-Initiating Cell Frequency
Authors: Yen Wan-Ching , Fischer Marcus M. , Axelrod Fumiko , Bond Christopher , Cain Jennifer , Cancilla Belinda , Henner William R. , Meisner Rene , Sato Aaron , Shah Jalpa , Tang Tracy , Wallace Breanna , Wang Min , Zhang Chun , Kapoun Ann M. , Lewicki John , Gurney Austin , Hoey Timothy 
Published: May 2015

Abstract
Purpose: The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling.
Experimental Design: We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts.
Results: We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature.
Conclusions: These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types. Clin Cancer Res; 21(9); 2084–95. ©2015 AACR.
Pembrolizumab for Treatment of Patients with Advanced or Unresectable Melanoma
Authors: Sullivan Ryan J. , Flaherty Keith T. 
Published: May 2015

AbstractFrom Coley's toxin to combination immune checkpoint inhibition, strategies to activate the immune system and generate anticancer immunity have been ongoing for well over a century. Over the past decade, the so-called immune checkpoint inhibitors, generally monoclonal antibodies that target key regulators of T-cell activation, emerged as the most effective immune-targeted agents. Pembrolizumab is the first anti-programmed death 1 (PD-1) antibody approved by the FDA for the treatment of metastatic melanoma. With responses seen in 25% to 40% of patients, depending on dose and setting (i.e., before or after ipilimumab), pembrolizumab specifically and anti–PD-1 antibodies generally are revolutionizing the treatment of melanoma. However, in the setting of other recent advances in the field, a number of practical issues are emerging that need to be addressed to optimize the care of patients with melanoma. First, the optimal sequencing of therapy (first-line immunotherapy over molecular targeted therapy, ipilimumab versus pembrolizumab as initial immune checkpoint inhibitor) is unknown and must be evaluated through randomized trials. Second, there is a strong rationale to combine immune checkpoint inhibitors (i.e., anti–PD-1 with ipilimumab) and to combine immune therapies with targeted therapy agents, so determining whether combination therapy is better than direct sequencing is another critical issue that needs to be addressed in carefully carried out studies. Clin Cancer Res; 21(13); 2892–7. ©2015 AACR.
Abstract 1016: Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and subsequently enhances angiogenesis in human chondrosarcoma cells
Authors: Lin Chih-Yang , Tang Chih-Hsin 
Published: May 2015

Abstract
Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.
Citation Format: Chih-Yang Lin, Chih-Hsin Tang. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and subsequently enhances angiogenesis in human chondrosarcoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2014-1016
Abstract 1018: The diarylpentanoid curcumin analog GO-Y078 can effectively inhibit tumor angiogenesis through actin disorganization
Authors: sugiyama shunsuke , Ishioka Chikashi , Shibata Hiroyuki 
Published: May 2015

Abstract
Background
Curcumin is a dietary pigment with anti-tumor potential. However, its bioavailability is low, and its numerous analogs are being developed. Diarylpentanoid analogs have approximately 50 times higher tumor suppression potential than curcumin and more effectively regulate various targets including β-catenin, nuclear factor-κB, and caspase-3.
Methods
Analogs were screened using endothelial cell sprouting and Xenopus vasculogenesis assays. Growth inhibition, apoptosis induction, wound healing, and invasion analyses as well as western blotting and cDNA microarrays were also performed. Stress fiber structures and focal adhesion (FA) were examined by immunohistochemistry. Subcellular analog localization was examined using a biotinylated analog.
Results
Sprouting and Xenopus assays indicated that GO-Y078 was comparable to the clinically approved angiogenesis inhibitors sorafenib and sunitinib. Inhibition against endothelial cell growth and migration and apoptosis induction of GO-Y078 were similar to or at most 20 times higher than those of sorafenib and sunitinib. However, inhibition of vascular endothelial growth factor (VEGF) signaling was much less than that observed with sorafenib and sunitinib. GO-Y078 inhibited actin stress fiber formation more effectively than sorafenib and sunitinib. It also decreased FA and induced detachment, resulting in anoikis. These potentials were suggested to be the result of mislocalization of heat shock protein 27 and actin as well as downregulation of fibronectin 1.
Conclusion
GO-Y078 is a new class of angiogenesis inhibitor that suppresses actin organization and vascular endothelial cell FA. Inhibition by these analogs could also be effective for redundancy due to complex angiogenesis signaling.
Citation Format: shunsuke sugiyama, Chikashi Ishioka, Hiroyuki Shibata. The diarylpentanoid curcumin analog GO-Y078 can effectively inhibit tumor angiogenesis through actin disorganization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1018. doi:10.1158/1538-7445.AM2014-1018
Abstract 1021: JFD, a novel small molecule for inhibiting vascular endothelial growth factor receptor-mediated angiogenesis
Authors: Dhandayuthapani Sivanesan , Rathinavelu Appu 
Published: May 2015

Abstract
Angiogenesis is the process of generating new capillary of blood vessels from an existing vasculature that plays a vital role in tumor growth and metastasis. Binding of vascular endothelial growth factor (VEGF) to tyrosine kinase receptor (VEGFR) is an important step for initiating vasculogenesis via. transphosphorylation of VEGF receptor associated tyrosine kinase. Therefore, blocking VEGFR or associated kinases has become a common strategy for arresting tumor angiogenesis. The newly discovered JFD is a novel anti-angiogenic agent that can limit the angiogenic capacity of endothelial cells and block tumor angiogenesis. The In vitro anti-angiogenesis potential of JFD was examined by ECMatrigelTM assay with Human umbilical vein endothelial cells (HUVEC) using different concentrations of JFD in the range of 0 - 10 µM. Among the different concentrations used, 1µM JFD significantly inhibited the angiogenesis when compared to control and a complete inhibition was observed at 10 µM concentration. Competitive binding of JFD against Fluorokine labeled VEGF for the same VEGFR was studied at 0.001 - 1.0 µM concentrations of JFD. A dose dependent inhibition of Fluorokine conjugated VEGF binding to its specific receptor in HUVEC cells was confirmed in our study. In the competition binding assay 1.0 µM concentration of JFD caused 93.5% inhibition of conjugated VEGF binding. The same 1.0 µM concentration of JFD was able to inhibit VEGF (10 ng/ml) induced phosphorylation of VEGFR2 in HUVEC cells. Furthermore, the potency of JFD as inhibitor of angiogenesis was experimentally proved by treating athymic nude mice that was implanted with GI-101A (human breast adenocarcinoma) xenograft tumor. Intraperitoneal injection of JFD at 12 mg/kg of body weight was able to significantly inhibit the tumor growth compared to the control group at different time periods. At the end of the treatment period 70% inhibition of tumor growth was observed in JFD treated animals along with prolongation of the survival. The plasma concentrations of JFD was also measured in Balb-C mice at different time periods (0 min - 180 min), using HPLC method. The data from both in vitro and in vivo study provide a strong basis for JFD to be used as a potent anti-angiogenic agent. (The financial support from the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida is gratefully acknowledged).
Citation Format: Sivanesan Dhandayuthapani, Appu Rathinavelu. JFD, a novel small molecule for inhibiting vascular endothelial growth factor receptor-mediated angiogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1021. doi:10.1158/1538-7445.AM2014-1021
Abstract 105: Establishment of imaging-based orthotopic tumor models for pharmacological evaluation of anticancer agents
Authors: Zhang Ning , Wang Wei , Meng Dan , Pan Jinjin , Jin Jing , Fan Yanxia , Jin Wenhao , Zhang Shuo , Chen Ze , Yang Xueqin , Wang Hongjun 
Published: May 2015

Abstract
Since its emergence in the mid 90's, the in vivo bioluminescent imaging (BLI) technology has been widely accepted by academia and pharmaceutical industry for research and pre-clinical drug development. The non-invasiveness and high sensitivity nature of BLI enables tumor lesions to be detectable far before they are palpable, allowing longitudinal tracking of tumors from their early development stages. BLI is particularly advantageous for monitoring systemic and orthotopic tumors that are not accessible by caliper measurement. Current preclinical evaluation of anti-cancer agents relies heavily on subcutaneous xenograft models. However, ectopically developed tumors in the subcutaneous tissue differ drastically in tumor stromata in aspects of cell contents and drug permeability, thus will often poorly predict pharmacological efficacy of the test agents. The notion that orthotopic models can better recapitulate the clinical tumor development and metastasis, thus better predict the clinical outcome of the anticancer drugs has gradually gained acceptance. Towards the development of better mouse models for pre-clinical drug development, we have established over twenty imaging based orthotopic tumor cell lines, including U87MG and AM38 brain tumors, HCT116, LoVo and SW620 colorectal cancers, A549 lung cancer, MSTO-211H mesothelioma, Raji and Namalwa lymphoma, MiaPaca-3 and Panc-1 pancreatic cancer, HepG2 liver cancer, and DU145 prostatic cancer. These tumor cells are extremely bright in luminescence emission, ranging from 1085 to 6397 photons/second/cell, thus allowing very sensitive detection in orthotopic tissues even with a few hundred cells. The tumorigenicity of the luciferase labeled cells has been validated in the pertinent orthotopic models. Evaluation of the responsiveness of some of the models to standard therapeutic agents has been conducted. In the U87MG orthotopic glioma model, we observed tumor regression in mice treated with temozolomide in a 5 mg/kg, po, q2d x 5 regimen. Current study of the orthotopic MSTO-211H mesothelioma model in response to standard clinical treatment drugs, such as pemetrexed, carboplatin and paclitaxel is in progress. It is expected that these imaging based orthotopic models will improve the pre-clinical pharmacological evaluation of anti-cancer agents and therefore better bridge the preclinical to clinical translation.
Citation Format: Ning Zhang, Wei Wang, Dan Meng, Jinjin Pan, Jing Jin, Yanxia Fan, Wenhao Jin, Shuo Zhang, Ze Chen, Xueqin Yang, Hongjun Wang. Establishment of imaging-based orthotopic tumor models for pharmacological evaluation of anticancer agents. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 105. doi:10.1158/1538-7445.AM2014-105
Abstract 1050: Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells
Authors: Gordian Edna , Welsh Eric , Muñoz-Antonia Teresita 
Published: May 2015

Abstract
Background: Transforming Growth Factor β (TGFβ) can induce Epithelial-to-Messenchymal Transition (EMT) in Non-Small Cell Lung Cancer (NSCLC) leading to increased potential to migrate and metastasize. A unique Tumor Promoting signature (TGFβ-TP97) with genes highly associated with TGFβ-induced EMT was derived from human lung cancer cell line microarray experiments. The TGFβ-TP97 EMT signature was then searched against the Connectivity Map (CMAP) dataset for drugs that induce gene expression changes opposite to those of the TGFβ-TP97 signature, and identified 17-DMAG as a compound that could potentially inhibit EMT in NSCLC cells. 17-DMAG is an Hsp90 inhibitor recently described to have a stronger antiproliferative effect in NSCLC harboring EGFR mutations over EGFR wild type lung cancers cells. Furthermore, 17-DMAG has been recently shown to prevent TGFβ induced fibrosis. Methods: A549 and A549T (A549 cells grown in the presence of TGFβ for over two weeks, that have acquired a mesenchymal/fibroblast-like phenotype) were treated with increasing concentrations of 17-DMAG, both in the absence and presence of 5ng/mL TGFβ, and proliferation was measured through GLO assay after 72 hours. The effects of 17-DMAG on TGFβ signaling was tested by Western Blotting for phosphorylated Smads and markers of TGFβ-induced EMT. 17-DMAG effects on morphology and migration were also determined through wound healing and invasion assays. Results: 1) A549T cells grown in TGFβ are more sensitive to the effects of 17-DMAG than cells grown without TGFβ; 2) Pre-treatment of A549 cells with 17-DMAG blocks the induction of EMT markers such as Snail and the downregulation of Ecadherin; 3) 17-DMAG blocks TGFβ-induced phosphorylation of SMAD2, SMAD3; and 4) 17-DMAG inhibits migration and decreases motility of A549 cells in the presence of TGFβ. Conclusion: These results show that 17-DMAG is a potent inhibitor of the effects of TGFβ-induced EMT in A549 cells. It interferes with the regulated process of TGFβ signaling by its ability to block Smad activation and induction of EMT proteins. These findings suggest that 17-DMAG can potentially be used in the treatment of NSCLC cells to prevent disease dissemination and invasion.
Citation Format: Edna Gordian, Eric Welsh, Teresita Muñoz-Antonia. Alvespimycin (17-DMAG) blocks TGFβ-induced EMT and migration in A549 lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2014-1050
Abstract 1051: Metastasis suppressor CD82 functions as a negative regulator in the adhesion-dependent epithelial-to-mesenchymal transition in prostate cancer cells
Authors: Byun Hee-Jung , Lee Yong-Sun , Jin Young-June , Lee Jae-Sub , Kim Young-Myeong , Lee Hansoo 
Published: May 2015

Abstract
Tetraspanin CD82 suppresses cancer metastasis by inhibiting cell motility and invasiveness. In an effect to reveal the mechanism underlying the metastasis-suppressing role of CD82, we here examined the effect of CD82 on epithelial-mesenchymal transition (EMT), a critical event of cancer cells that promotes migration and invasion. In human prostate cancer cell lines, an increase in CD82 expression levels by exogenous gene delivery elevated E-cadherin levels, but decreased the levels of mesenchymal cell proteins including Snail, Twist, vimentin, N-cadhherin, and α-smooth muscle actin, suggesting EMT-suppressing role of CD82. Also, increased CD82 expression resulted in decreased motility and invasiveness of prostate cancer cells. In contrast, CD82 knockdown decreased E-cadherin levels, but increased the levels of mesenchymal cell proteins, together with cell morphology change to fibroblast-like shape. CD82 also interfered with TGF-β1- and Wnt-induced EMT. Additionally, CD82 decreased expression of β-catenin target genes such as c-myc and cyclin D1 by inhibiting nuclear translocation of β-catenin. Notably, the negative effect of CD82 on EMT was apparent on cells adhered to fibronectin. Fibronectin-binding α3β1/α5β1 integrins were involved in CD82-mediated inhibition of EMT. Importantly, human prostate cancer tissue specimens displayed a positive correlation of CD82 with E-cadherin expression levels, along with a negative correlation of CD82 with vimentin levels. Moreover, both CD82 and E-cadherin levels were inversely correlated with the malignant progression stages of human prostate cancers. Taken together, these results strongly suggest that CD82 suppresses motility and invasiveness of prostate cancer cells by inhibiting EMT in an α3β1/α5β1 integrin-dependent manner.
Citation Format: Hee-Jung Byun, Yong-Sun Lee, Young-June Jin, Jae-Sub Lee, Young-Myeong Kim, Hansoo Lee. Metastasis suppressor CD82 functions as a negative regulator in the adhesion-dependent epithelial-to-mesenchymal transition in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1051. doi:10.1158/1538-7445.AM2014-1051
Abstract 1091: CCR4+ regulatory T cells progressively accumulate in the presence of leukocyte-derived CCL22/CCL17 in an experimental model of glioblastoma multiforme
Authors: Chang Alan L. , Wainwright Derek A. , Dey Mahua , Han Yu , Lesniak Maciej S. 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. One hallmark of GBM is the accumulation of infiltrating regulatory T cells (Tregs), a highly immunosuppressive T cell subset that suppresses T cell-mediated GBM rejection. Previous work has demonstrated that the Treg-recruiting chemokine, CCL22, is expressed by patient-resected GBM. Importantly, the number of Tregs expressing CCR4, the cognate chemokine receptor for CCL22 and CCL17, is increased in the peripheral blood of GBM patients. To investigate the therapeutic potential of targeting the CCR4 chemokine-receptor axis in brain tumors, we performed FACS analysis to determine the level of CCR4-expressing Tregs and other T cell populations. In addition, we analyzed the mRNA expression levels of the Treg-recruiting chemokines CCL22 and CCL17 in different cellular populations by Percoll gradient isolation followed by qRT-PCR. Using the orthotopic GL261 model of GBM, we found a progressive accumulation of CCR4+ Tregs in the brain tumor. Coincidently, the expression of CCL17 and CCL22 was predominantly localized to the tumor-infiltrating leukocytes, rather than the tumor tissue itself. Finally, we tested the potential impact of a CCR4 antagonist on Treg recruitment and CD8+/Foxp3+ T cell ratio. We found that CCR4 antagonist treatment was able to increase the CD8+/Foxp3+ T cell ratio during the early time points post-GL261 injection. These results implicate the chemokine receptor CCR4 as a therapeutic target for further investigation as a potential strategy to target Treg trafficking to GBM.
Citation Format: Alan L. Chang, Derek A. Wainwright, Mahua Dey, Yu Han, Maciej S. Lesniak. CCR4+ regulatory T cells progressively accumulate in the presence of leukocyte-derived CCL22/CCL17 in an experimental model of glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1091. doi:10.1158/1538-7445.AM2014-1091