bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5358: IL-4/IL-13 induce Duox2/DuoxA2 expression and reactive oxygen production in human pancreatic and colon cancer cells
Authors: Wu Yongzhong , Doroshow James H. 
Published: May 2015

Abstract
NADPH oxidase (NOX)-derived reactive oxygen species (ROS) contribute significantly to inflammation-associated carcinogenesis. Expression of dual oxidase 2 (Duox2), one of seven members of the NOX gene family, is up-regulated in inflammatory bowel disease, chronic pancreatitis, and in many human malignancies including carcinomas of the prostate, lung, and breast. Previously, we demonstrated that Stat1 and/or NF-κB play a critical role in modulating the enhanced expression of Duox2, and its cognate maturation factor DuoxA2, by IFN-γ and lipopolysaccharide in human pancreatic cancer cells. This cytokine-mediated increase in Duox2 expression is responsible for a consequent significant increase in tumor cell H2O2 production and DNA damage. Using Caco2 and T84 human colon cancer lines, and BxPC-3 pancreatic cancer cells, we now report that two other pro-inflammatory cytokines, IL-4 and IL-13, also strongly induce Duox2/DuoxA2 RNA and protein expression (&gt;5-10-fold after 24h treatment with 50 ng/ml cytokine). In the BxPC-3 line, IL-4 exposure activates the Stat6 signaling pathway, enhances expression of Duox2/DuoxA2 in a time- and concentration-dependent manner, and leads to a significant increase in the generation of extracellular H2O2. The transcription and translation inhibitors actinomycin D and cyclohexamide both individually suppress IL-4-induced Duox2 expression, suggesting that IL-4-mediated Duox2 up-regulation is transcriptionally regulated, but that new protein synthesis is also necessary. We found that Stat6 is essential for IL-4-induced Duox2 expression because silencing Stat6 with Stat6-specific siRNA significantly attenuates IL-4-induced Duox2 RNA and protein levels in BxPC-3 cells. To evaluate the potential role of Duox2 in inflammation-associated human cancers further, immunohistochemical studies were performed to semi-quantitatively examine Duox expression using human pancreatic and colon cancer tissue arrays. We found that a majority of samples of pancreatic intra-epithelial neoplasia and frank pancreatic cancer demonstrated high-level expression of Duox , often in association with inflammatory cell infiltrates; high-level Duox expression was also found in most colorectal cancer samples. These studies, in concert with our previous experiments, strongly suggest that ROS, produced as a consequence of cytokine-induced Duox up-regulation, may be associated with the development of inflammation-related gastrointestinal malignancies.
Note: This abstract was not presented at the meeting.
Citation Format: Yongzhong Wu, James H. Doroshow. IL-4/IL-13 induce Duox2/DuoxA2 expression and reactive oxygen production in human pancreatic and colon 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 5358. doi:10.1158/1538-7445.AM2014-5358
Abstract 5387: Dual kinase/bromodomain inhibitors for rationally designed polypharmacology
Authors: Quinn Elizabeth R. , Ciceri Pietro , Müller-Knapp Susanne , O'Mahony Alison , Fedorov Oleg , Filippakopoulos Panagis , Hunt Jeremy P. , Lasater Elisabeth A. , Pallares Gabriel , Picaud Sarah , Wells Christopher , Wodicka Lisa M. , Shah Neil P. , Knapp Stefan , Treiber Daniel K. 
Published: May 2015

Abstract
Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multi-target profile has, however, necessitated the application of combination therapies, which can pose significant clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as novel targets for cancer therapy. Here we have used BROMOscan™ bromodomain ligand binding assays to identify several clinical kinase inhibitors that also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase/bromodomain inhibitors. Nanomolar activity on BRD4 by clinical PLK1 and JAK2/FLT3 kinase inhibitors is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a novel strategy for rational single agent polypharmacological targeting. Importantly, cell-based data show that these dual inhibitors suppress c-Myc expression (a hallmark of BRD4 inhibition) and induce complex polypharmacological phenotypes reflecting dual kinase/bromodomain inhibition across a panel of primary human cell assay systems that model complex tissue and disease state environments (BioMap™). Furthermore, rich structure-activity relationships for related inhibitors and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase/bromodomain inhibitors.
Citation Format: Elizabeth R. Quinn, Pietro Ciceri, Susanne Müller-Knapp, Alison O'Mahony, Oleg Fedorov, Panagis Filippakopoulos, Jeremy P. Hunt, Elisabeth A. Lasater, Gabriel Pallares, Sarah Picaud, Christopher Wells, Lisa M. Wodicka, Neil P. Shah, Stefan Knapp, Daniel K. Treiber. Dual kinase/bromodomain inhibitors for rationally designed polypharmacology. [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 5387. doi:10.1158/1538-7445.AM2014-5387
Abstract 5390: Development of a high-throughput screening assay to identify UHRF1 inhibitors via time-resolved fluorescence resonance energy transfer (TR-FRET)
Authors: Walker David A. , Wyhs Nicolas , Giovinazzo Hugh , Yegnasubramanian Srinivasan , Nelson William G. 
Published: May 2015

Abstract
Aberrant DNA methylation of gene promoters can be involved in silencing tumor suppressor genes in cancer. The protein ubiquitin-like containing PHD and ring finger domains 1 (UHRF1) is an essential component in the cellular machinery for DNA methylation maintenance and can couple DNA methylation and other epigenetic histone modifications. UHRF1 is thought to bind newly synthesized hemimethylated DNA and recruit DNA methyltransferases to copy the methylation pattern to the daughter DNA strand. Interfering with the ability of UHRF1 to bind methylated DNA can lead to the re-expression of epigenetically silenced genes including tumor suppressors, which positions UHRF1 as a target for anticancer drug development. We have created a high-throughput, time-resolved fluorescence resonance energy transfer (TR-FRET)-based assay to screen for inhibitors capable of disrupting the interaction between the UHRF1 SRA domain and hemi-methylated DNA. The assay measures the degree of TR-FRET between a 5′-fluorescein (FAM) labeled hairpin oligonucleotide and a terbium-conjugated antibody bound to the 6xHis-tag of the UHRF1_SRA domain polypeptide. In 384-well plate format, the assay achieved a Z' factor of 0.74. We successfully screened the Library of Pharmacologically Active Compounds (LOPAC) for inhibitors of UHRF1_SRA binding to hemimethlylated DNA, and validated 6 hit compounds in a dose-response series. These include: aurintricarboxylic acid, NF449, 6-hydroxy-DL-DOPA, NF023, PPNDS and mitoxantrone. Additionally, we observed a decrease in methylation one week after treatment of DU145 cells with mitoxantrone at a concentration near its IC50 from the TR-FRET binding assay. This suggests that mitoxantrone, a known DNA topoisomerase II poison and general DNA intercalator, may interfere with methylation maintenance. In summary, we have established a novel method to identify small molecule inhibitors of the UHRF1-methylated DNA interface, and have shown that one hit compound, mitoxantrone, can perturb methylation maintenance near its IC50 for inhibition of SRA domain binding to methylated DNA.
Citation Format: David A. Walker, Nicolas Wyhs, Hugh Giovinazzo, Srinivasan Yegnasubramanian, William G. Nelson. Development of a high-throughput screening assay to identify UHRF1 inhibitors via time-resolved fluorescence resonance energy transfer (TR-FRET). [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 5390. doi:10.1158/1538-7445.AM2014-5390
Abstract 5399: A novel treatment for triple-negative breast cancer using intrinsic magnetized paclitaxel
Authors: Umemura Masanari , Makino Ayako , Sato Itaru , Feng Xianfeng , Oda Kayoko , Ohtake Makoto , Izuka Satoshi , Iwai Maki , Matsuo Kosuke , Eguchi Haruki , Ishikawa Yoshihiro 
Published: May 2015

Abstract
Background: We previously reported the identification of a novel nano-organic compound, EI236, an anti-cancer agent with intrinsic magnetic property. In addition to anti-cancer effect, its ferromagnetic property contributes to unique features.1) It can be attracted by a magnet. 2) It can be visualized by magnetic resonance imaging (MRI). Hereby, we have identified the key mechanism that contributes to magnetism by X-ray crystallographic analysis, and succeeded in generating a novel paclitaxel with intrinsic magnetism; this is a single paclitaxel compound, and is not a paclitaxel encapsulated in micelle with magnetic particles. Our aim is to examine its effect on triple negative-breast cancer (TNBC) cells. Material and Method: The magnetization of the magnetized paclitaxel was measured with a superconducting quantum interference device (SQUID) (Quantum Design MPMS7 system). Breast cancer cells, MDA-MB-453 (TNBC) and MCF7 (Non-TNBC), were obtained from RIKEN Bioresource center. Cell proliferation assay was performed using a commercially available kit, XTT Cell Proliferation Assay Kit. Apoptotic cells were stained with Annexin V, allophycocyanin conjugate and 7-amino-actinomycin D, and measured by fluorescence activated cell sorting (FACS), to evaluate early and late apoptosis. Cell cycle analysis was performed using The Cycletest™ Plus DNA Reagent Kit and assessed using FACS. Results: Plots of magnetization versus magnetic field revealed that the magnetized paclitaxel exhibits magnetic property in SQUID. Magnetized paclitaxel was easily attracted by a commercial bar magnet. Magnetized paclitaxel exhibits greater anti-cancer effect than original paclitaxel in TNBC and Non-TNBC cells in a dose-dependent manner. Magnetized paclitaxel induced apoptosis and G2/M arrest in cell cycle analysis in a dose-dependent manner, suggesting that magnetized paclitaxel retained the original anti-cancer property. In MRI T2 -weighted imaging, signal intensity was changed in a concentration-dependent manner with magnetized paclitaxel, but not with commercial available paclitaxel. Conclusion: These results suggested that various conventional anti-cancer drugs might be similarly magnetized, leading to novel drug development in future cancer chemotherapy.
Citation Format: Masanari Umemura, Ayako Makino, Itaru Sato, Xianfeng Feng, Kayoko Oda, Makoto Ohtake, Satoshi Izuka, Maki Iwai, Kosuke Matsuo, Haruki Eguchi, Yoshihiro Ishikawa. A novel treatment for triple-negative breast cancer using intrinsic magnetized paclitaxel. [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 5399. doi:10.1158/1538-7445.AM2014-5399
Abstract 5519: Investigation of the cellular mechanisms of action of maximiscin, a novel natural product with selective cytotoxic activity against a triple negative breast cancer molecular subtype
Authors: Robles Andrew J. , Du Lin , King Jarrod B. , Cichewicz Robert H. , Mooberry Susan L. 
Published: May 2015

Abstract
Natural products have historically been an excellent resource for new pharmaceuticals, particularly anticancer agents. Fungi are a remarkable source of novel secondary metabolites that have never been evaluated for their therapeutic potential. However, a vast majority of fungal species found in diverse environments are inaccessible to research scientists. We recently isolated and identified the natural product maximiscin from a Tolypocladium sp. isolate obtained through a crowdsourcing initiative. This compound showed in vitro cytotoxic potency against multiple cancer cell lines in the NCI-60 in vitro screening panel and in vivo antitumor efficacy against a UACC-62 melanoma xenograft model. MDA-MB-468, a triple negative breast cancer (TNBC) cell line of the basal-like 1 (BL1) subtype, was found to be particularly sensitive to the cytotoxic effects of maximiscin compared to several other TNBC cell lines. This finding suggests maximiscin modulates a cellular signaling pathway that specifically drives the BL1 subtype of TNBC. In this study we investigated the cellular mechanisms of action of maximiscin using cell biological and biochemical approaches. The effects of maximiscin on cell cycle distribution were evaluated and maximiscin reduced the fraction of cells in the S and G2/M phases of the cell cycle, and began to induce apoptosis within 8 h. Intracellular signaling through multiple pathways was evaluated by immunoblotting, providing an indication of potential mechanisms of action. Maximiscin also circumvented P-glycoprotein-mediated multidrug resistance. These studies suggest maximiscin may have therapeutic potential for the treatment of BL1 TNBC, especially in cases where P-glycoprotein-mediated multidrug resistance has developed. Studies are ongoing to further characterize the cellular and antitumor effects of maximiscin in BL1 models.
Citation Format: Andrew J. Robles, Lin Du, Jarrod B. King, Robert H. Cichewicz, Susan L. Mooberry. Investigation of the cellular mechanisms of action of maximiscin, a novel natural product with selective cytotoxic activity against a triple negative breast cancer molecular subtype. [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 5519. doi:10.1158/1538-7445.AM2014-5519
Abstract 609: Targeting IGF-I receptor for hepatocellular carcinoma
Authors: Adachi Yasushi , Matsunaga Yasutaka , Yamamoto Hiroyuki , Nosho Katsuhiko , Suzuki Hiromu , Arimura Yoshiaki , Endo Takao , Kato Yasuo , Carbone David P. , Shinomura Yasuhisa 
Published: May 2015

Abstract
Aims; Hepatocellular carcinoma (HCC) is one of worse prognostic diseases. Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and tumor development of many malignancies and is thought to be a next molecular target. We have previously shown successful therapy for gastrointestinal carcinomas, including colon, stomach, esophageal, pancreatic, and biliary tract cancers, using recombinant adenoviruses expressing dominant negative IGF-IR (IGF-IR/dn). In this study, we want to assess the roles of IGF axis on HCC and to develop potential targeted therapeutics for HCC.
Methods; We assessed mRNA expressions of IGFs and those receptors in HCC cell lines. We assessed the effect of IGF-IR blockade on signal-transduction, growth, apoptosis-induction, and migration. To block IGF signals, we used IGF-IR/dn, short hairpin RNA, monoclonal antibody, and tyrosin kinase inhibitor for IGF-IR.
Results; IGF-I messages expressed in 63%, IGF-II mRNA in 44%, and IGF-IR in 89% of HCC cell lines. All IGF-IR blockades suppressed significantly both in vitro cell growth and colony formation. Each anti-IGF-IR up-regulated both stressor- and chemotherapy-induced apoptosis. IGF-IR inhibitor down-regulated cell migration. IGF-IR targeting strategies effectively blocked ligands induced receptor activation and the downstream signals.
Conclusions; IGF axis might play a key role in tumor progression of human HCC. Every strategy to block IGF-IR shows a useful anticancer therapeutic for HCC, indicating that IGF-IR may be a candidate molecular target for HCC.
Citation Format: Yasushi Adachi, Yasutaka Matsunaga, Hiroyuki Yamamoto, Katsuhiko Nosho, Hiromu Suzuki, Yoshiaki Arimura, Takao Endo, Yasuo Kato, David P. Carbone, Yasuhisa Shinomura. Targeting IGF-I receptor for hepatocellular carcinoma. [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 609. doi:10.1158/1538-7445.AM2014-609
Abstract CT218: Wilms′ tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer
Authors: Koido Shigeo , Nishida Sumiyuki , Homma Sadamu , Takeda Yutaka , Komita Hideo , Morita Satoshi , Ito Toshinori , Morimoto Soyoko , Oka Yoshihiro , Yanagisawa Satoru , Toyama Yoichi , Ikegami Masahiro , Nagano Hiroaki , Ohkusa Toshifumi , Tajiri Hisao , Sugiyama Haruo 
Published: May 2015

Abstract
Wilms′ tumor gene 1 (WT1) protein is an attractive target for cancer immunotherapy. To investigate the feasibility of a combination therapy consisting of gemcitabine and WT1 peptide for patients with advanced pancreatic cancer, 32 HLA-A*24:02-positive patients were enrolled. HLA-A*24:02-restricted, modified 9-mer WT1 peptide (3 mg) emulsified with Montanide ISA51 adjuvant (WT1 vaccine) was injected intradermally biweekly. Moreover, gemcitabine (1,000 mg/m2) was administrated on days 1, 8, and 15 of a 28-day cycle. Median survival time and one-year survival rate were 8.1 months and 29%, respectively. The association between longer survival and positive delayed-type hypersensitivity (DTH) to WT1 peptide alone was statistically significant, and longer survivors featured a higher frequency of memory-phenotype WT1-specific cytotoxic T-lymphocytes (CTLs) before and during treatment. In conclusion, the combination therapy was well-tolerated and promising treatment for advanced pancreatic cancer. DTH-positivity to WT1 peptide alone and a higher frequency of memory-phenotype WT1-specific CTLs could be useful predictive markers for clinical efficacy.
Citation Format: Shigeo Koido, Sumiyuki Nishida, Sadamu Homma, Yutaka Takeda, Hideo Komita, Satoshi Morita, Toshinori Ito, Soyoko Morimoto, Yoshihiro Oka, Satoru Yanagisawa, Yoichi Toyama, Masahiro Ikegami, Hiroaki Nagano, Toshifumi Ohkusa, Hisao Tajiri, Haruo Sugiyama. Wilms′ tumor gene 1 (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. [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 CT218. doi:10.1158/1538-7445.AM2014-CT218
Abstract CT330: Adjusting for confounding effects of treatment crossover in a randomized phase 2 study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma
Authors: Latimer Nicholas , Amonkar Mayur , Stapelkamp Ceilidh , Sun Peng 
Published: May 2015

Abstract
In a randomized phase 2 study (BRF113220), dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) improved progression-free survival (HR=0.39; 95% CI, 0.25-0.62; P&lt;.001) vs dabrafenib alone. 54 patients were randomized to each arm. At the most recent data cut (March 2013), median duration of follow-up was 24 months and 52% of patients had died. ITT analyses of overall survival (OS) are likely to underestimate the true benefit of treatment because patients in the control arm (83%) were able to cross over to combination treatment upon progression. ITT median OS, a secondary endpoint, was 23.8 vs 20.2 months (HR=0.73; 95% CI, 0.43-1.24). We adjusted for confounding due to this crossover using randomization-based crossover adjustment methods: the rank-preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE) algorithm. Different assumptions about the durability of treatment effect were tested: “treatment group” analyses allow for a treatment effect that continues beyond treatment discontinuation, while “on treatment_observed” analyses assumed that the treatment effect disappears upon discontinuation. Results are presented in the Table. Reestimation of median OS following adjustment with both RPSFTM and IPE (possible only for the treatment group analyses) suggested an OS gain of 9.1 months with combination treatment vs dabrafenib alone (compared with a 3.6-month gain under ITT assumptions). The RPSFTM estimation method performed marginally better than the IPE analyses and may provide more robust results. After adjusting for the effect of crossover, the reduction in HRs to 0.47-0.50 suggests that the ITT analysis underestimates the effect of dabrafenib plus trametinib on OS. Results are uncertain due to the limiting assumptions associated with the RPSFTM and IPE methodology, small trial size, low number of observed deaths, and low number of control group patients who did not cross over.
Crossover Adjustment MethodAssumptionOS HR (95% CI)None (ITT analysis unadjusted for crossover)0.73 (0.43-1.24)RPSFTMTreatment group0.47 (0.13-1.66)On treatment–observed analyses0.49 (0.15-1.63)IPETreatment group0.50 (0.16-1.54)On treatment–observed analyses0.47 (0.14-1.61)
Citation Format: Nicholas Latimer, Mayur Amonkar, Ceilidh Stapelkamp, Peng Sun. Adjusting for confounding effects of treatment crossover in a randomized phase 2 study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma. [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 CT330. doi:10.1158/1538-7445.AM2014-CT330