bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3229: Drug repurposing of topiramate in obesity-driven endometrial cancer
Authors: Tran Arthur-Quan , Sullivan Stephanie A. , Zhou Chunxiao , Kaufman David , Bae-Jump Victoria 
Published: July 2017

Abstract
Introduction: Topiramate (TPM) is a B-D-fructopyranose sulfamate that acts by inhibiting carbonic anhydrases (CAs) and has been implicated as a novel inhibitor of angiogenesis. TPM is commonly used for the treatment of epilepsy and migraine headaches; however, when combined with phentermine, TPM can induce weight loss. Due to its weight loss and anti-angiogenic properties, we assessed TPM’s potential as an anti-tumorigenic agent in endometrial cancer (EC), a highly obesity-driven disease.
Methods: Cell proliferation was assessed by MTT assay after exposure to TPM for 72 hours in the HEC-1A, KLE, Ishikawa and ECC-1 EC cell lines. Two representative cell lines, ECC-1 and Ishikawa, were used to analyze apoptosis, cell cycle progression, cell adhesion and invasion. Apoptosis was analyzed by Annexin V-FITC assay. Inhibition of adhesion and invasion by TPM were assessed by ELISA and transwell assay, respectively. Cell cycle progression was evaluated by Cellometer. Western immunoblotting was performed to assess downstream targets of the MAPK and mTOR pathways. The LKB1fl/flp53fl/fl EC mouse model was utilized to assess the in vivo effects of TPM. AdCre was injected at six weeks of age to induce invasive EC. Eight wks following AdCre injection, mice (N=10 per group) were treated with placebo or TPM (200 mg/kg/day, oral) for four weeks. The expression of phosphorylated-S6 and Ki-67 was assessed by IHC.
Results: TPM inhibited cell proliferation in a dose dependent manner in all four EC cell lines (IC50 range=1500-3000 mM). Treatment with TPM resulted in G1 arrest and induction of apoptosis (p&lt;0.05). TPM also reduced adhesion and invasion in the EC cell lines (p=0.05), with a corresponding decrease in VEGF expression. In addition, TPM significantly inhibited phosphorylation of p42/44 and S6 in the EC cell lines. Lastly, TPM decreased tumor weight in the LKB1fl/flp53fl/fl mice by 68% compared to those treated with placebo (p&lt;0.05), accompanied by a reduction in Ki-67 and phosphorylated-S6 expression (p&lt;0.05).
Conclusion: TPM inhibited cell proliferation and tumor growth in EC cell lines and an EC mouse model. Therefore, TPM may be worthy of drug repurposing as an anti-tumorigenic agent in EC, with the potential added benefit of weight loss in this obesity-linked disease.
Citation Format: Arthur-Quan Tran, Stephanie A. Sullivan, Chunxiao Zhou, David Kaufman, Victoria Bae-Jump. Drug repurposing of topiramate in obesity-driven endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3229. doi:10.1158/1538-7445.AM2017-3229
Abstract 3233: Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition
Authors: Chi Ya-Hui , Chang Chun-Ping , Ke Yi-Yu , Lin Wen-Hsing , Hsieh Hsing-Pang 
Published: July 2017

Abstract
Guided by computational modeling addressing the back pocket of Aurora kinases, several novel chemical analogs of BPR1K653 were designed and synthesized in two steps with 30-66% yields. All synthesized compounds were evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays, cellular phosphorylation inhibition assays and cell viability assays. Of them, compound 3a that exhibits no substitution at phenylurea showed similar inhibition activity to Aurora-A and -B. Compounds 3b and 3c which harbor tertiary amino group at meta position of phenylurea showed 10-15 fold inhibition selectivity for Aurora-A over Aurora-B in enzymatic assays. In addition, 3b and 3c were more than 200 fold superior in inhibiting T-loop autophosphorylation of Aurora-A compared to Aurora-B in HCT116 colon carcinoma cells. On the other hand, compound 3d with a 4-hydroxypiperidinyl group at ortho position preserves Aurora-B inhibition activity. Molecular docking study revealed that the various steric interaction between the compound and residues in the back pocket of Aurora kinases determines their inhibition selectivity.
Citation Format: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Hsing-Pang Hsieh. Design and synthesis of BPR1K653 and its derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3233. doi:10.1158/1538-7445.AM2017-3233
Abstract 3240: Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents
Authors: Yawson Emmanuel , Garcia Angel , Dhari Husamuldeen , Rajnarayanan Rajendram V. 
Published: July 2017

Abstract
Triple negative breast cancer (TBNC) is the only major type of breast cancer for which no specific FDA approved target therapy is available to improve patient outcomes. TNBC lacks the usual breast cancer targets estrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor. Studies have shown that TBNC does express the epidermal growth factor receptor and has recently emerged as one of the potential targets in TBNC. Epidermal growth factor (EGF) mediates several cellular functions and processes such as survival, motility, differentiation, proliferation and death. When it is released by epidermal tissues, EGF binds to cell surface receptors such as the Epidermal growth factor receptor (EGFR) causing a conformational change which facilitates its dimerization. This receptor dimerization triggers its tyrosine kinase-mediated signal transduction activity. Apart from EGF, EGFR is reported to bind to Transforming growth factor alpha (TGF-α), Argos and Potato Carboxypeptidase inhibitor (PCI). All of these proteins have unique structural motifs which targets EGFR. PCI’s structure consisting of three disulfide bridges presents a unique knot like binding motif resembling EGF and is able to compete with EGF for its binding site on EGFR preventing receptor dimerization thereby antagonizing its action. We have used an integrated computational drug discovery approach to generate several PCI derived peptidic ligands targeting EGFR protein-protein interactions. PCI- peptides bind to EGFR in silico and block EGFR-mediated cell growth, proliferation and migration in vitro. We believe these designer peptidic inhibitors will provide structural and mechanistic clues towards novel therapeutics to combat TNBC.
Citation Format: Emmanuel Yawson, Angel Garcia, Husamuldeen Dhari, Rajendram V. Rajnarayanan. Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3240. doi:10.1158/1538-7445.AM2017-3240
Abstract 3242: Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters
Authors: Obara Megumi , Ohnuma Shinobu , Chufan Eduardo E. , Ishida Masaharu , Kudoh Katsuyoshi , Sugisawa Norihiko , Ohtsuka Hideo , Naitoh Takeshi , Shibata Hiroyuki , Iwabuchi Yoshiharu , Ambudkar Suresh V. , Unno Michiaki 
Published: July 2017

Abstract
Cancer patients often develop resistance to anticancer drugs. ATP-binding cassette (ABC) transporter-mediated drug efflux is one of the mechanisms responsible for development of resistance to anticancer drugs. The present study investigates the use of curcumin, a natural product and a dietary constituent of turmeric, which inhibits the function of three ABC drug transporters including ABCB1, ABCC1 and ABCG2. However, limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinic. We focused on curcumin analogs that were synthesized at Tohoku University and have been shown to exhibit higher bioavailability than natural curcumin to test whether the synthetic analogs also inhibit the function of ABC drug transporters. To investigate this, KB-V1 and K562/BCRP cell lines overexpressing ABCB1 and ABCG2 were used for the experiments. For these studies, we screened nineteen synthetic analogs of curcumin for their effect on the transport function of ABCB1 and ABCG2 by flow cytometry. Four curcumin analogs, GO-Y030, GO-Y078, GO-Y168 and GO-Y172 inhibited efflux of mitoxantrone mediated by ABCG2 and sensitized ABCG2-expressing K562 leukemic cells to the anticancer drug, SN-38 in cell toxicity assays. Some of the curcumin analogs (GO-Y030, GO-Y078, GO-Y172) stimulated ATPase activity of ABCG2 at nanomolar concentrations (EC50 = 480 ± 0.06, 790 ± 0.10, 930 ± 0.12 nM). In addition, GO-Y030, GO-Y078, GO-Y168, GO-Y172 analogs also inhibited photolabeling of ABCG2 in MCF-7-FL plasma membranes with iodoarylazidoprazosin, which is transported by this transporter. These data demonstrate that similar to curcumin, synthetic curcumin analogs also interact at the drug-binding pocket of ABCG2. In aggregate, these results suggest that non-toxic synthetic curcumin analogs with increased bioavailability may be useful to reverse ABCG2-mediated resistance to anticancer agents.
Citation Format: Megumi Obara, Shinobu Ohnuma, Eduardo E. Chufan, Masaharu Ishida, Katsuyoshi Kudoh, Norihiko Sugisawa, Hideo Ohtsuka, Takeshi Naitoh, Hiroyuki Shibata, Yoshiharu Iwabuchi, Suresh V. Ambudkar, Michiaki Unno. Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3242. doi:10.1158/1538-7445.AM2017-3242
Abstract 3248: Identification and optimization of a highly active, cross reactive Complex-1 inhibitor
Authors: Mowat Jeffrey , Christian Sven , Sperl Carolyn , Ehrmann Alexander , Menz Stephan , Guenther Judith , Hillig Roman , Bauser Marcus , Haegebarth Andrea , Schwede Wolfgang 
Published: July 2017

Abstract
Mitochondria are key regulators of both energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, potentially providing an opportunity for selectively targeting tumor cells.
Based on a high throughput screen (HTS), we identified new, albeit moderately active, lead structures with cross reactivity between mouse and human Complex 1. SAR elaboration of the lead structure allowed for optimization of the potency, although compounds still suffered from low metabolic stability. Further improvement of the in vitro and in vivo PK properties finally permitted in vivo animal studies. Herein, we report for the first time the preclinical profile and structure of a highly active, optimized, human/mouse cross-reactive Complex I inhibitor that allowed for the further investigation into the therapeutic potential of Complex I inhibition in cancer.
Citation Format: Jeffrey Mowat, Sven Christian, Carolyn Sperl, Alexander Ehrmann, Stephan Menz, Judith Guenther, Roman Hillig, Marcus Bauser, Andrea Haegebarth, Wolfgang Schwede. Identification and optimization of a highly active, cross reactive Complex-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2017-3248
Abstract 3252: Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents
Authors: Henderson Elizabeth , Gangapuram Madhavi , Eyunni Suresh , Redda Kinfe , Ardley Tiffany 
Published: July 2017

Abstract
Chronic inflammation is believed to promote cancer through cellular and genomic damage. Inflammation creates a microenvironment within the tissue that enhances cell proliferation. In 2016, American Cancer Society estimates that 1,685,210 new cancer cases are expected to be diagnosed in the United States. Cyclooxygenase (COX) is an enzyme found to play an essential role in inflammation and converts arachidonic acid to prostaglandin-like molecules. The three isomers of COX are COX-1, COX-2, and COX-3. COX-2 has been found to be up-regulated in inflammation and some cancers, such as breast cancer and prostate cancer. Tetrahydropyridines (THPs) developed by our research group were effective in inhibiting inflammation, COX, and the growth of some breast cancer cells. Previous research has shown that pharmacological activities of the THP derivatives depend greatly on the nature and position of the substituents on the THP ring structure. Here, we present the synthesis of a series of novel THP derivatives. 3-Ethylpyridine is reacted with O-mesitylenesulfonylhydroxylamine (O-MSH) to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines. Five novel N-substituted [benzoylamino]-3-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The evaluation of these compounds cytotoxicity studies on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell lines, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay is underway.
This research was supported by the National Center for Research Resources and the National Institute of Minority Health and Health Disparities of the National Institutes of Health through Grant Number 8 G12MD007582-28.
Citation Format: Elizabeth Henderson, Madhavi Gangapuram, Suresh Eyunni, Kinfe Redda, Tiffany Ardley. Synthesis of N-substituted [Benzoylamino]-3-Ethyl-1,2,3,6-tetrahydropyridines as potential anti-cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2017-3252
Abstract 3254: Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach
Authors: Das Viswanath , Fürst Tomáš , Gurská Soňa , Džubák Petr , Hajdúch Marián 
Published: July 2017

Abstract
Two-dimensional (2D) cultures of immortalized cancer cells have played a significant role cancer drug discovery and development process for decades. However, the limitations imposed by the long-term cultures of cancer cell lines are becoming increasingly apparent only recently. Therefore, there is a general shift towards three-dimensional (3D) cell cultures, which effectively mimic tumor complexities, for lead optimization and to accelerate translation research. 3D cell cultures not only model the in vivo architecture of tumors, but 3D-derived cells also retain numerous signatures of cancer stem cells compared to parental cells in 2D.
In this study, using a unified 2D and 3D cell culture screening approach, we screened the LOPAC library from Sigma-Aldrich as a proof-of-concept study. The drug screening was performed using parental colorectal cancer HCT116 cells as a model cell line. 3D-derived cultures were generated from multicellular spheroids of HCT116 cells. Additionally, utilizing lightsheet fluorescence microscopy (LSFM), we studied the tissue penetration of drugs in spheroids of HCT116 and cells expressing hypoxia-inducible factor-1α (HIF-1α).
We identified cc. 200 compounds from the LOPAC library that showed increased activity in 3D-derived cultures. A dose–response relationship study of top 20% compounds further confirmed the preferential activity of these drugs in 3D than 2D cultures. Next, studies in spheroid cultures resulted in the identification of five lead compounds with potent spheroid-size reducing effects. Three of these compounds were kinase inhibitors, one HIF-1α inhibitor, and one interestingly, a monoamine oxidase inhibitor. LSFM studies in HCT116-HIF-1α spheroids showed that two kinase inhibitors and the HIF-1α inhibitors significantly altered spheroid hypoxia, and presumably spheroid growth. We believe that this proof-of-concept study will further highlight the advantages of a combined 2D/3D screening approach for drug discovery and development, and consequently enable downstream testing at reduced cost.
Citation Format: Viswanath Das, Tomáš Fürst, Soňa Gurská, Petr Džubák, Marián Hajdúch. Identification of potent anti-tumor agents from the LOPAC library using a unified 2D/3D cell culture screening approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3254. doi:10.1158/1538-7445.AM2017-3254
Abstract 3257: Molecular characterization of the human stomach microbiota in gastric cancer patients
Authors: Yu Guoqin , Torres Javier , Hu Nan , Medrano-Guzman Rafael , Herrera-Goepfert Roberto , Humphrys Michael S. , Wang Lemin , Wang Chaoyu , Ding Ti , Ravel Jacques , Taylor Philip R. , Abnet Christian , Goldstein Alisa 
Published: July 2017

Abstract
Background Helicobacter pylori (Hp) is the primary cause of gastric cancer but we know little of its relative abundance and other microbes in the stomach, especially at the time of gastric cancer diagnosis. Here we characterized the taxonomic and derived functional profiles of gastric microbiota in 157 non-malignant gastric tissue samples from two different sets of gastric cancer patients, and compared them with microbial profiles of oral, stool, nasal, vagina and skin samples from Human Microbiome Project.
Results We show that Hp is the most abundant member of gastric microbiota in both Chinese and Mexican samples (51% and 24% respectively), followed by the genera commonly seen in the oral microbiota. Taxonomic (phylum) profiles of stomach microbiota largely resembled oral microbiota when the Helicobacter reads were removed. The functional profiles of stomach microbiota, however, were distinct from those found in other body sites and had higher inter-subject dissimilarity. Gastric microbiota composition did not differ by Hp colonization status or stomach anatomic site, but did differ between paired non-malignant and tumor tissues in either Chinese or Mexican samples.
Conclusions Our study is the first to show that Hp is the dominant member of the gastric microbiota in many gastric cancer patients rather than diminished or depleted as traditionally believed. Our results provide insights on the gastric microbiota composition and function in gastric cancer patients, which may have important clinical implications.
Citation Format: Guoqin Yu, Javier Torres, Nan Hu, Rafael Medrano-Guzman, Roberto Herrera-Goepfert, Michael S. Humphrys, Lemin Wang, Chaoyu Wang, Ti Ding, Jacques Ravel, Philip R. Taylor, Christian Abnet, Alisa Goldstein. Molecular characterization of the human stomach microbiota in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2017-3257
Abstract 3263: Is Latin America ready for the use of genomics in cancer care and control
Authors: Perdomo Sandra , Torres Angela , Olivier Javier , Frecha Cecilia , Quezada-Urban Rosalía , Díaz-Velasquez Clara Estela , Vaca Felipe 
Published: July 2017

Abstract
In Latin American (LA) countries cancer is the second most frequent cause of death after cardiovascular disease. Disease patterns have changed from infectious to chronic, the population is increasing and becoming elderly, and countries lack planning to respond adequately to this epidemiological and socio-demographic transition. By 2025 and increment of nearly 30% of new cases and 35% of deaths from cancer are predicted. Genomic studies have profoundly changed cancer management from improved cancer diagnosis to reformulating cancer prognosis and treatment. However, all these key advances have been mainly concentrated in highly developed nations and little is known about the capacities and needs of cancer genomics in the LA context. In order to evaluate the capacity and development of cancer genomics in LA, we collected available information for all countries in Central, South America and Cuba. Data reviewed included: number of NGS platforms, number of cancer research institutions, research groups working in cancer genetics, publications on cancer genetics and genomics in the last 10 years, educational programs on genomics and related national cancer control policies. Currently, there are a total of 212 NGS platforms in LA. Mexico and Brazil are the countries with more users, and Peru and Ecuador have the fewest. 118 research groups in South America have been working in cancer genetics and started developing cancer genomics related projects. No data on research groups was available for countries in Central America. In the last 10 years, 231 articles in cancer genetic/genomic related topics were published by authors affiliated to LA institutions. Educational programs in genomics are scarce, almost exclusive of graduate programs and few applied to cancer. Twelve countries in LA have national cancer control plans (NCCP). All NCCPs reviewed consider secondary prevention strategies for early diagnosis, opportune treatment and decrease of mortality, areas where genomic analysis could be implemented. Only 5 NCCPs include cancer research as an action plan to increase cancer prevention strategies and reduce both incidence and mortality. Despite the recent advances in introducing cancer genomics knowledge and application in LA, the region lacks development of integrated genomic research projects, improved use of platforms, associated educational programs and health policies that might focus on the most frequent cancers and could impact cancer care.
Citation Format: Sandra Perdomo, Angela Torres, Javier Olivier, Cecilia Frecha, Rosalía Quezada-Urban, Clara Estela Díaz-Velasquez, Felipe Vaca. Is Latin America ready for the use of genomics in cancer care and control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3263. doi:10.1158/1538-7445.AM2017-3263