bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A141: A novel inhibitor of malignant signaling in metastatic breast cancer
Authors: Humphries-Bickley Tessa , Castillo-Pichardo Linette , Borrero-Garcia Luis , Forestier-Roman Ingrid , Cubano Luis , Hernandez-O'Farrill Eliud , Vlaar Cornelis , Dharmawardhane Suranganie 
Published: May 2016

Abstract
The Rho GTPase Rac is a pivotal regulator of cancer cell migration and invasion; processes required for metastatic progression. We previously characterized the small molecule EHop-016 as a novel Rac inhibitor in metastatic breast cancer cells and recently reported that EHop-016 was effective at reducing tumor growth, metastasis, and angiogenesis in nude mice at 25 mg/kg bodyweight (BW) (Castillo-Pichardo, et al. 2014). We also determined the pharmacokinetics and bioavailability of EHop-016, and reported that EHop-016 is rapidly cleared from mouse plasma with a half-life of ∼5 hrs and ∼30% bioavailability (Humphries-Bickley, et al., 2015). To improve the bioavailability and efficacy of EHop-016, we synthesized and screened a number of derivatives, from which EHop-016A was identified as a potent Rac inhibitor at nM concentrations. Moreover, as determined from immunofluorescence and brightfield microscopy of several breast cancer cell lines, EHop-016A has a dramatic effect on cell morphology by inducing a loss of cell polarity, and inhibiting cell surface actin-based extensions and focal adhesions, to ultimately result in the detachment of cells from the extracellular matrix (ECM). In addition, EHop-016A reduces breast cancer cell migration in a transwell assay. EHop-016A also decreases mammosphere formation, indicating an inhibitory effect on breast cancer stem cell-like properties. The effect of EHop-016A on metastatic cancer cell viability was determined via MTT assays. EHop-016A decreases cell viability with a GI50 of 150 nM and 110 nM in MDA-MB-435 and MDA-MB-231 human metastatic cancer cell lines respectively. Western blotting demonstrated that EHop-016A decreases anti-apoptotic proteins BCL-2 and BCL-xL without affecting their gene expression, as quantified by qPCR. Consequently, EHop-016A increases pro-apoptotic caspase 3/7 activity. These results indicate that the EHop-016A induced cell rounding and detachment from the substratum results in anoikis (apoptosis due to dissolution of integrin-mediated cell to ECM attachments). Therefore, this new small molecule compound has potential as an inhibitor of metastatic breast cancer progression, and warrants further investigation as an anticancer agent.
Citation Format: Tessa Humphries-Bickley, Linette Castillo-Pichardo, Luis Borrero-Garcia, Ingrid Forestier-Roman, Luis Cubano, Eliud Hernandez-O'Farrill, Cornelis Vlaar, Suranganie Dharmawardhane. A novel inhibitor of malignant signaling in metastatic breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A141.
Abstract A146: Study of anti-leukemia activity of N-(1-pyrenlyl) maleimide in vivo using a bioluminescent mouse model
Authors: Wang Tzu-Chien , Chang Pei-Chi , Chen Chi-Yuan 
Published: May 2016

Abstract
Telomerase plays a pivotal role in cellular immortality and tumorigenesis. Telomerase activity is normally not detectable in most somatic cells, but is activated in the vast majority of cancer cells. Therefore, inhibition of telomerase has been viewed as a promising anticancer approach due to its specificity for cancer cells. During a search for anticancer drugs by screening for small molecules of telomerase inhibitors, we have identified a very promising compound, N-(1-pyrenyl) maleimide, which displays the greatest differential cytotoxicity against hematopoietic Jurkat-T cells in vitro. In this study, we examined the anticancer activity of N-(1-pyrenyl) maleimide against human T-cell acute lymphoblastic leukemia (T-ALL) in vivo. Human T- ALL cells, such as Jurkat cells, were transfected with luciferase-expressing plasmid to establish luciferase-expressing T-ALL cells. The luciferase-expressing T-ALL cells were mixed with matrigel and injected subcutaneously into the nude mice. We have successfully employed such a xenograft method to establish a bioluminescent mouse model for investigating the anti-leukemia activity of N-(1-pyrenyl) maleimide and other classical anti-leukemia drugs. Using the established bioluminescent mouse model, we have begun to examine the anticancer activity of N-(1-pyrenyl) maleimide against T-ALL. We will present our most updated findings in this meeting. (Supported by grant CMRPD3D0171 from Chang Gung Memorial Hospital)
Citation Format: Tzu-Chien Wang, Pei-Chi Chang, Chi-Yuan Chen. Study of anti-leukemia activity of N-(1-pyrenlyl) maleimide in vivo using a bioluminescent mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A146.
Abstract A152: Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro
Authors: Ross Sarah , Collins Scott , Jovanovic Jelena , Kendrew Jane , Barry Simon , Rathanaswami Swami , David Blakey , Weir Hazel 
Published: May 2016

Abstract
Autotaxin (ATX) is a secreted phosphodiesterase that cleaves lysophosphatidylcholine (LPC) in serum to produce lysophosphatidic acid (LPA). LPA can signal through a family of GPCR receptors to mediate cell proliferation, migration and survival in cancer cells. Blocking the enzymatic activity of ATX is proposed to have anti-tumour activity by reducing levels of LPA and preventing signaling through the LPA receptor family. A number of synthetic inhibitors have been developed to understand the role in ATX in driving carcinogenesis and these encompass lipid substrate mimetics as well as inhibitors identified from small molecule library screens. Some of these compounds demonstrate low nM activity in vitro and a subset have shown some in vivo activity although none have progressed into the clinic. We sought to identify novel selective ATX antibodies with low nM affinity, which fully inhibited ATX enzyme activity of human, cyno and mouse ATX protein. Using an ATX enzyme inhibition assay we identified and characterised two ATX antibodies, 9E10 and 18B7 which, interestingly, had different binding mechanisms of inhibition and showed potent cross-species inhibition of ATX in vitro. We measured human and mouse ATX expression levels across of panel of xenograft models and verified ATX activity by measuring cleavage of an ATX substrate using conditioned media from these cells. 9E10 and 18B7 antibodies were shown to inhibit the activity of secreted ATX and prevent cleavage of an ATX substrate. 9E10 and 18B7 showed significant inhibition of LPC stimulated cell growth and IL-8 secretion in a range of ATX and/or LPA responsive tumour cell lines. In ex vivo plasma ATX activity assays, treatment of mouse or human plasma with the ATX antibodies inhibited the increase in LPA levels that are observed over time when serum samples are incubated at 37°C. In summary we have identified highly selective ATX antibody inhibitors which will be useful tools to explore the role of ATX in tumour growth and invasion.
Citation Format: Sarah Ross, Scott Collins, Jelena Jovanovic, Jane Kendrew, Simon Barry, Swami Rathanaswami, Blakey David, Hazel Weir. Novel autotaxin inhibitory antibodies block lysophosphatidic acid production in plasma and tumour cell proliferation in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A152.
Abstract A16: Boosting of in vivo hollow fiber assay by using luciferase-labeled tumor cell lines
Authors: Schaefer-Obodozie Cynthia , Leisegang Ulrike , Ruf Susanne , Giesen Bianca , Schaechtele Christoph , Weber Holger 
Published: May 2016

Abstract
In drug development, predicting in vivo inhibitory drug activity from cellular assay data is difficult due to the complexity of the living system, resulting in the sacrifice of many mice in vain. In order to prescreen compounds for their in vivo activity more efficiently, the hollow fiber assay (HFA) was developed in 1995 by Hollingshead et al. The HFA assay allows the simultaneous evaluation of multiple cell lines implanted in separated drug-(but not cell-) permeable fibers within a single mouse. We herein report on the advancement of this technology by use of luciferase-labeled tumor cell lines. The limits of detection are boosted and disturbing (non-labeled) stroma cells attached to the fibers are excluded enabling a clear separation of drug effects on the tumor cells.
The effect of Gemcitabine and Paclitaxel on growth of luciferase-labeled MDA-MB-231 and A549 cells in HFA was analyzed by MTT in comparison to luciferase activity analysis. The general findings between both read-outs were comparable. The growth of MDA-MB-231 cells was inhibited by both, Paclitaxel and Gemcitabine, whereas inhibition of A549 cell growth was only observed under Paclitaxel treatment. T/C calculation for the MTT analysis predicted a partial response in all cases. In contrast, the luciferase activity analysis clearly distinguished between a complete response for MDA-MB-231 cell growth when treated with Paclitaxel and Gemcitabine and a partial response for Paclitaxel on A549 cell growth. These results correspond to the in vivo xenograft studies: T/C for Gemcitabine using MDA-MB-231 cells was 2-fold lower (16.2%) than T/C in A549 tumors using Paclitaxel (36.3%). In addition, results are shown applying this technology for up to 42 days instead of the typical 14 days, enhancing the possibility to analyze slow-acting drugs.
In summary, the HFA assay for in vivo drug screening with luciferase-labeled tumor cells remarkably increases the power and predictability for drug efficacy in xenograft studies.
Citation Format: Cynthia Schaefer-Obodozie, Ulrike Leisegang, Susanne Ruf, Bianca Giesen, Christoph Schaechtele, Holger Weber. Boosting of in vivo hollow fiber assay by using luciferase-labeled tumor cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A16.
Abstract A170: Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in bladder cancer harboring FGFR3-fusion or -mutation
Authors: Suzuki Tomoyuki , Kikuchi Aya , Nakazawa Taisuke , Iizuka Masateru , Nakayama Ayako , Kameda Minoru , Shindoh Nobuaki , Terasaka Tadashi , Hirano Masaaki , Kuromitsu Sadao 
Published: May 2016

Abstract
Background: Fibroblast growth factor (FGF) / FGF receptor (FGFR) gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers. Recently, FGFR3 fusions (FGFR3-TACC3 and FGFR3-BAIAP2L1), which have potent oncogenic activity, have been discovered in bladder and lung cancer. FGFR kinase inhibitors are expected to be a targeted therapy for bladder cancer harboring FGFR3 gene alternations. A phase I clinical trial of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, is ongoing (NCT02038673). Method: We tested selectivity of ASP5878 among 128 kinases and sensitivity of ASP5878 on cell proliferation of bladder cancer cell lines. FGFR3 and ERK phosphorylation in FGFR3-dependent bladder cancer cell lines were evaluated with sandwich ELISA or Western blotting. In vivo antitumor effects of ASP5878 were examined in subcutaneously implanted bladder cancer cell lines in nude mice. Results: Among 128 kinases, only 9 kinases including wild-type FGFR1-4 and FGFR3/4 mutants were inhibited more than 50% by ASP5878 (200 nmol/L). The IC50 values of ASP5878 against FGFR1, 2, 3 and 4 kinases are 0.47, 0.60, 0.74 and 3.5 nmol/L, respectively. In addition, ASP5878 suppressed cell growth in several cancer cell lines harboring FGF / FGFR gene alternations. Among 25 bladder cancer cell lines, ASP5878 selectively inhibited cell proliferation of UM-UC-14 [FGFR3 (S249C) positive], RT-112 (FGFR3-TACC3 positive), RT-4 (FGFR3-TACC3 positive) and SW780 (FGFR3-BAIAP2L1 positive). FGFR3 and ERK phosphorylation in UM-UC-14 and RT-112 cell lines were inhibited by ASP5878 in a concentration-dependent manner. Furthermore, ASP5878 inhibited cell proliferation of gemcitabine-resistant RT-112 cells and adriamycin-resistant UM-UC-14 cells. Once-daily oral administration of ASP5878 induced tumor regression at 1 and 3 mg/kg in UM-UC-14 and RT-112 xenograft models, respectively, without body weight loss. Conclusions: These findings suggest that ASP5878 has the potential to be an oral targeted therapy against bladder cancer harboring FGFR3-TACC3 fusion or FGFR3 point mutation even after the acquisition of chemoresistance.
Citation Format: Tomoyuki Suzuki, Aya Kikuchi, Taisuke Nakazawa, Masateru Iizuka, Ayako Nakayama, Minoru Kameda, Nobuaki Shindoh, Tadashi Terasaka, Masaaki Hirano, Sadao Kuromitsu. Preclinical antitumor activity of ASP5878, a novel inhibitor of FGFR1, 2, 3 and 4, in bladder cancer harboring FGFR3-fusion or -mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A170.
Abstract A177: Repositioning Bazedoxifene as a novel inhibitor of IL-6/GP130 signaling for pancreatic cancer therapy
Authors: Wu Xiaojuan , Xiao Hui , Li Chenglong , Lin Jiayuh 
Published: May 2016

Abstract
This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:15 PM ET Friday, November 6.
Citation Format: Xiaojuan Wu, Hui Xiao, Chenglong Li, Jiayuh Lin. Repositioning Bazedoxifene as a novel inhibitor of IL-6/GP130 signaling for pancreatic cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A177.
Abstract A180: Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity
Authors: Irie Takayuki , Asami Tokiko , Sawa Ayako , Taniyama Chika , Funakoshi Yoko , Uno Yuko , Masai Hisao , Sawa Masaaki 
Published: May 2016

Abstract
Introduction&gt;
Cell cycle kinases have been recognized as potential anticancer targets, because loss of regulated cell cycle progression would lead to uncontrolled cell growth and development of cancer. Cdc7 kinase is involved in regulation of the cell cycle and plays important roles in DNA replication. Notably, inhibition of Cdc7 in cancer causes lethal S phase or M phase progression, whereas normal cells can survive, most likely through induction of cell cycle arrest at the DNA replication checkpoints. Therefore Cdc7 kinase has emerged as a promising therapeutic target for the treatment of cancers. Here we present a novel series of furanone derivatives with potent inhibitory effects on Cdc7 kinase.
&lt;Methods&gt;
To identify hit compounds that are insensitive or resistant to high ATP concentration, a high-throughput screening (HTS) was performed in the presence of 100 microM ATP which corresponds to 36-times higher than the Km value of ATP for Cdc7 kinase activity. To characterize inhibitors, ATP dependency and pre-incubation effects were examined. To determine the efficacy of Cdc7 inhibitors, phosphorylation of MCM2 protein in cells were analyzed by western blotting. Selected compounds were subjected to a kinase selectivity panel assay.
&lt;Results&gt;
Only a single hit compound was identified from the HTS, reflecting extremely low hit rate compared to that of other kinase targets in our past HTS. Subsequent hit to lead studies led to the identification of a novel furanone compound as a potential lead compound for further optimization study. Interestingly, these furanone derivatives showed slow-binding inhibition against Cdc7, and exhibited strong inhibitory activity for Cdc7 even in the presence of 1 mM ATP that was added after the pre-incubation of the kinase and compound. Notably this pre-incubation effect was not observed with other kinases tested. Detailed results using cancer cells will also be presented in this poster.
Citation Format: Takayuki Irie, Tokiko Asami, Ayako Sawa, Chika Taniyama, Yoko Funakoshi, Yuko Uno, Hisao Masai, Masaaki Sawa. Discovery of furanone derivatives as novel Cdc7 inhibitors with anti-tumor activity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A180.
Abstract A184: Activity of plinabulin in tumor models with Kras mutations
Authors: Lloyd George Kenneth , Du Lihua , Lee Gloria , Dalsing-Hernandez Jessica , Kotlarczyk Kari , Gonzales Paul , Nawrocki Steffan , Carew Jennifer , Huang Lan 
Published: May 2016

Abstract
Kras mutations, particularly at codons 12 and 13, are reported to occur in up to one-third of human cancer cells and are considered to be undruggable targets (Stoize et al, 2015). These mutations are especially prevalent in NSCLC and CRC. Plinabulin is a new chemical entity in Phase 3, with a multi-faceted mechanism of action, including anti-angiogenesis, inhibition of tubulin polymerization and activation of JNK, which is downstream of the Kras pathway. The combination of these vascular mechanisms together with activity downstream from Kras, suggests that plinabulin could express anti-tumor activity in the presence of Kras mutations. The present report summarizes the findings with plinabulin on tumors with Kras mutations (p.12V, p.12D, p.D153V, p.G12A, p.G12C, p.G12D, p.G12V or p.G13D) in vitro and in vivo.
In vitro, plinabulin was very potent (IC50 7-33 nM) as a cytotoxic agent against CRC cell lines containing a Kras mutation at p.G13D (LoVo, HCT-15, HCT116) or a BRAF + P53 mutation (HT-29) and against multiple myeloma cell lines (Singh et al, Blood, 2010) with either Nras or p.G12A mutations (IC50&lt;10nM). The active metabolite of irinotecan (SN-38) was less active (2-30 fold) in the CRC cell lines.
In vivo, plinabulin was tested as a single agent and in combination with SOC in the CRC Kras mutation murine models LoVo and HCT-15 and the P53/Braf mutant model HT-29, the NSCLC Kras mutation model A549, the multiple myeloma Kras mutation model MM.1S and the breast Kras mutation model MDA-MB-231. As a single agent plinabulin was at most moderately active in these models, with the greatest activity seen in the LoVo, HCT-15, and MDA-MB-231 models (TGI 21-43%); the exception was a marked single agent activity observed in the MM.1S model. However, in all cases plinabulin significantly increased the anti-tumor activity of the standard of care agents (TGI 59-84%, with several CRs and increased tolerability as compared to SOC alone).
In summary, plinabulin exhibits a potent anti-tumor activity either in vitro, or in vivo as a single agent or in combination with SOC agents. This activity is observed across several tumor types and mutations, but the spectrum of activity does not extend across all tumor types (e.g. inactive in vivo in Kras mutations for pancreatic cancer or melanoma). These findings are encouraging in terms of clinical studies in Kras mutations in MM, NSCLC, CRC and breast cancers.
Citation Format: George Kenneth Lloyd, Lihua Du, Gloria Lee, Jessica Dalsing-Hernandez, Kari Kotlarczyk, Paul Gonzales, Steffan Nawrocki, Jennifer Carew, Lan Huang. Activity of plinabulin in tumor models with Kras mutations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A184.
Abstract A197: Cancer associated fibroblasts are not form by epithelial-to-mesenchymal transition in nu/nu mice
Authors: Szabo Pavol , Smetana Karel , Dvorankova Barbora , Mateu Rosana , Rihova Blanka 
Published: May 2016

Abstract
Cancer-associated fibroblasts are very important players to form specific cancer microenvironmnet and bioactive elements influencing the biological properties of malignant tumors. Their origin from different cell types has been established. It is suppose and under debate that exist three ways of the possibility of their formation: a) by epithelial-to-mesenchymal transition from cancer cells b) by activation of local mesenchymal cells c) by MSC (mesenchymal stem cell), which migrate from bone marrow to tumor. We focused on epithelial-to-mesenchymal transition. This study shows that human cancer cells lines FaDu FaDu (human squamous cell carcinoma isolated from pharynx; HTB-43), Sw620 (human colorectal adenocarcinoma; CCL-227) and HT-29 (human colorectal adenocarcinoma; HTB-38) grafted to nu/nu CD-1 mice induced formation of tumor stroma with the presence of typical smooth muscle actin-containing cancer-associated fibroblasts. These cells seem to be of the host origin because they are not recognized by an antibody specific for human vimentin, as was also verified in vitro. These results suggest that cancer-associated stromal fibroblasts are not formed by epithelial-to-mesenchymal transition from cancer cells.
Citation Format: Pavol Szabo, Karel Smetana, Barbora Dvorankova, Rosana Mateu, Blanka Rihova. Cancer associated fibroblasts are not form by epithelial-to-mesenchymal transition in nu/nu mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A197.
Abstract A198: A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis
Authors: Li Yongsheng 
Published: May 2016

Abstract
Hypoxia and intracellular Ca2+ transient are fundamental traits of cancer. Signaling cascades initiated or regulated by HIF-1 is essential for hypoxic responses. Stromal-interaction molecule 1 (STIM1) is well known as a Ca2+ sensor on endoplasmic reticulum (ER) that mediates SOCE activation and promotes tumor invasion and migration. However, there was no general consensus about the relationship between HIF-1 and STIM1. Also, the significance of STIM1, as well as the Ca2+ mobilization route in cancer cells during hypoxia remains unknown. Our results show that STIM1 correlates with elevated hypoxia-inducible factor-1 alpha (HIF-1α) in hypoxic hepatocarcinoma cells (HCC) and is upregulated during hepatocarcinoma growth. HIF-1 directly transcripts STIM1 and contributes to store-operated Ca2+ entry (SOCE), while STIM1-mediated SOCE is also required for HIF-1 accumulation in hypoxic HCC, via activating Ca2+/calmodulin-dependent protein kinase II and p300. Administration of YC-1, a HIF-1 inhibitor, or knockdown of HIF1A significantly diminishes hypoxia-enhanced STIM1 and suppresses tumorigenesis. Moreover, ectopic expression of STIM1 or HIF-1α partially reverses the impaired growth of the tumor treated with YC-1. These results suggest a mutual dependency and regulation of STIM1 and HIF-1 in controlling Ca2+ mobilization and hypoxic tumor growth, and highlight a potential target for early hypoxia-related intervention.
Citation Format: Yongsheng Li. A novel regulatory circuit involving STIM1 and HIF-1 mediates hypoxia-driven hepatocarcinogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A198.