tbuckley/cabot-search huggingface dataset:
Abstract 2468: Gene aberrations for precision medicine against lung adenocarcinoma
Authors: Motonobu Saito, Koji Kono, Takashi Kohno
Journal: Cancer Research (2017)

Abstract Lung adenocarcinoma (LADC) is often triggered by an aberration in a driver oncogene. LADC harboring EGFR mutation and ALK fusion can be treated with anti-cancer drugs that target the aberrant gene products. These molecularly targeted drugs showed significant positive effectiveness for the LADC patients with EGFR mutations and ALK fusions. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such “druggable” driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in several clinical trials. On the other hand, about 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. In this presentation, we show gene mutation profiles according to driver oncogenes and summarize the frequencies of those aberrations. We also compare driver aberrations between Japan and USA according to smoking status and sex. This will provide the current status of research on precision medicine against LADC and enumerates the research priorities for the near future. Citation Format: Motonobu Saito, Koji Kono, Takashi Kohno. Gene aberrations for precision medicine against lung adenocarcinoma [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 2468. doi:10.1158/1538-7445.AM2017-2468
Abstract 5424: Metformin increases PDH and suppresses HIF1A under hypoxic conditions and induces cell death in oral squamous cell carcinoma
Authors: Talita Guimarães, Lucyana Farias, Carlos Fraga, Alfredo De Paula, Sergio Santos, Ricardo Gomez, Andre Guimaraes
Journal: Cancer Research (2017)

Abstract Background: Metformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells. Objective: The present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment. Methods: PDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses. Results: Low PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3. Conclusions: In conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions. Note: This abstract was not presented at the meeting. Citation Format: Talita Guimarães, Lucyana Farias, Carlos Fraga, Alfredo De Paula, Sergio Santos, Ricardo Gomez, Andre Guimaraes. Metformin increases PDH and suppresses HIF1A under hypoxic conditions and induces cell death in oral squamous cell carcinoma [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 5424. doi:10.1158/1538-7445.AM2017-5424
Abstract 2818: PDX model of the enriched pleural effusion from advanced lung cancer patient for testing on targeted drug sensitivity and resistance
Authors: Feifei Zhang, Ke Wang, Wenhua Xu, Yang Yang, Kedong Ouyang, Shun Lu, Danyi Wen, Taiping Chen
Journal: Cancer Research (2017)

Abstract Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often developing resistance to the early sensitive drug treatment. Surgery tumor tissues are usually not available to establish patient derived xenograft (PDX) models which is critical to evaluate drug sensitivity and resistance. We applied CD45 magnet beads to enrich the tumor cell population from pleural effusion specimens of advanced lung cancer. Seven PDX models were successfully established in this way. Based on genetic profiling of these models, TKI drug related EGFR mutations and ALK fusion were confirmed (EGFR: L858R, T790M, Exon 19 insertion; ALK fusion). Further in vivo efficacy studies were designed to test on multiple drug sensitivity and resistance including Gefitinib, Erlotinib, Ceritinib, Alectinib, AZD9291. Tumor growth inhibition (TGI) were well matched with corresponding gene mutations among the models. In particularly, T790M model was resistant to Erlotinib and quite sensitive for AZD9291. In conclusion, the models established here are very useful to test on potency of many current investigational TKI drugs and provide base for drug resistant model establishment. Citation Format: Feifei Zhang, Ke Wang, Wenhua Xu, Yang Yang, Kedong Ouyang, Shun Lu, Danyi Wen, Taiping Chen. PDX model of the enriched pleural effusion from advanced lung cancer patient for testing on targeted drug sensitivity and resistance [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 2818. doi:10.1158/1538-7445.AM2017-2818
Reply to Francesco Araco et al.’s Letter to the Editor re: Marzio Angelo Zullo, Francesco Plotti, Marco Calcagno, Elettra Marullo, Innocenza Palaia, Filippo Bellati, Stefano Basile, Ludovico Muzii, Roberto Angioli and Pierluigi Benedetti Panici. One-Year Follow-up of Tension-free Vaginal Tape (TVT) and Trans-obturator Suburethral Tape from Inside to Outside (TVT-O) for Surgical Treatment of Female Stress Urinary Incontinence: A Prospective Randomised Trial. Eur Urol 2007;51:1376–84
Authors: Marzio Angelo Zullo, Francesco Plotti, Marco Calcagno, Elettra Marullo, Innocenza Palaia, Filippo Bellati, Stefano Basile, Ludovico Muzii, Roberto Angioli, Pierluigi Benedetti Panici
Journal: European Urology (2007)
Abstract SY28-02: The adipose-cancer link: From microenvironment to metabolomics
Authors: Cornelia M. Ulrich
Journal: Cancer Research (2017)

Abstract This presentation will showcase the interface of systemic and localized disturbances in metabolism with tumor development, specifically focusing on colorectal cancer. Colorectal cancer is the second leading cause of cancer-related death worldwide among both men and women. Risk and preventive factors are well established and include, among others, lack of physical activity and obesity (risk) as well as aspirin use and screening (prevention). Adipose tissue is emerging as a key player in carcinogenesis through the secretion of proinflammatory cytokines and adipokines. The colon is surrounded by adipose tissue, which supports the direct (paracrine) adipose-colon crosstalk and influence as a tumor microenvironment, as well as systemic influences on colon carcinogenesis factors secreted into the bloodstream. As part of the ColoCare cohort, an international, multicenter cohort of colorectal cancer patients, we have investigated adipose tissue distribution, composition, characteristics, and possible influence on colorectal tumors. In an integrated analysis of the transcriptome and metabolome of visceral and subcutaneous adipose tissue (VAT and SAT, respectively), we showed that there are distinct differences that may play a central role in driving carcinogenesis (1). These analyses are ongoing and have been extended to blood-based measures of the inflammasome and metabolome, as well as tumor characteristics. Adipose tissue biology can also be directly affected by weight-loss interventions through diet and exercise. As part of the Nutrition and Exercise in Women (NEW) study, we showed that weight loss results in changes in adipose tissue gene expression as well as corresponding reductions in biomarkers, including inflammatory biomarkers (2, 3). References 1. Liesenfeld DB, Grapov D, Fahrmann JF, Salou M, Scherer D, Toth R, et al. Metabolomics and transcriptomics identify pathway differences between visceral and subcutaneous adipose tissue in colorectal cancer patients: the ColoCare study. Am J Clin Nutr 2015;102(2):433-43. 2. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, et al. Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 2012;72(9):2314-26. 3. Campbell KL, Foster-Schubert KE, Makar KW, Kratz M, Hagman D, Schur EA, et al. Gene expression changes in adipose tissue with diet- and/or exercise-induced weight loss. Cancer Prev Res 2013;6(3):217-31. Citation Format: Cornelia M. Ulrich. The adipose-cancer link: From microenvironment to metabolomics [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 SY28-02. doi:10.1158/1538-7445.AM2017-SY28-02
Abstract 439: Metabolic flux analysis reveals targets to sensitize chemoresistance in acute myeloid leukemia induced by mesenchymal stromal cell-derived exosomes
Authors: Abhinav Achreja, Hongyun Zhao, Ziwen Zhu, Jonathan Gerszberg, Marina Y. Konopleva, Michael Andreeff, Deepak Nagrath
Journal: Cancer Research (2017)

Abstract The tumor microenvironment has a pleiotropic role in supporting cancer cell growth, metastasis and drug resistance. Exosomes from mesenchymal stromal cells (MSC) were found to regulate metabolism of acute myeloid leukemia (AML) cells that led to a chemoresistant phenotype. Exosomes carry a host of proteins, nucleotides and metabolites that can induce metabolic reprogramming recipient cells via direct supply of metabolite cargo or through signaling. We utilized 13C tracer techniques and two metabolic flux analysis techniques to reveal the mechanism of metabolic reprogramming induced by MSC-derived exosomes. First, 13C metabolic flux analysis was used to quantify intracellular fluxes of central carbon, amino acids and fatty acid metabolism in AML cells cultured with and without exosomes in media with 13C substrates. Second, we employed a novel technique, exosome-mediated metabolic flux analysis (Exo-MFA), to estimate direct support provided by metabolite supply from exosome cargo by introducing 13C-labeled exosomes. The combined analysis dissected the metabolite supply from exosome cargo from the overall reprogramming of metabolic pathways due to exosomes. Our results revealed key metabolic pathways that could be targeted to inhibit exosome-induced reprogramming to reverse the chemoresistant phenotype. Citation Format: Abhinav Achreja, Hongyun Zhao, Ziwen Zhu, Jonathan Gerszberg, Marina Y. Konopleva, Michael Andreeff, Deepak Nagrath. Metabolic flux analysis reveals targets to sensitize chemoresistance in acute myeloid leukemia induced by mesenchymal stromal cell-derived exosomes [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 439. doi:10.1158/1538-7445.AM2017-439
Abstract 359: C1GALT1 activates multiple RTKs and promotes malignant behaviors in pancreatic adenocarcinoma cells
Authors: Ting-Chun Kuo, Hsueh-Fen Juan, Yu-Wen Tien, Min-Chuan Huang
Journal: Cancer Research (2017)

Abstract Pancreatic adenocarcinoma (PDAC), stands up to the 4th in all cancer mortalities and remains the most in progress in America. Curative resection remains the most and only potential strategy but only 15~20% of patients are candidates. Even though, many of them have dismal prognosis. Aberrant glycosylation illustrates an attribution of cancer, especially fot promoting malignant behaviors in adenocarcinomas. Altered expression of glycans, such as GalNAcα1-O-S/T (Tn antigen) and Galβ1,3-GalNAc-S/T (T antigen), is hallmark of cancers. Core 1 β1,3-galactosyltransferase (C1GALT1) catalyzes the transfer of Gal to Tn antigen to form T antigen. C1GALT1 is reported to contribute to clinicopathological features and malignant phenotypes in various cancers. However, the expression and function of C1GALT1 in PDAC remain unrevealed. Our data showed that C1GALT1 was overexpressed in PDAC tissues and correlated with poor prognosis. C1GALT1 knockdown inhibited viability, migration, and invasion analyzed by MTT, transwell migration, and Matrigel invasion assays, respectively, in PDAC cells, associated with increased Tn antigen but decreased T antigen expression. Conversely, C1GALT1 overexpression promoted these malignant behaviors. C1GALT1 knockdown inhibited AKT and ERK activities in PDAC cells. Consistently, phospho-receptor tyrosine kinase (p-RTK) array showed decreased phosphorylation of several RTKs including EGFR, IGF1R, and FLT3. Additionally, flow cytometry of C1GALT1 knockdown cells showed enhanced apoptosis, which was associated with decreased catalase, Bcl-x, and death receptor DR5 revealed by apoptosis array. We also found that C1GALT1 knockdown arrested G1 progression in PDAC cells. Furthermore, gene set enrichment analysis of cDNA microarray indicated that C1GALT1 regulated cell cycle, cytoskeleton, and chromatin structure in PDAC cells. These findings indicate that higher C1GALT1 expression predicts worse survival of PDAC and enhances malignant characters in PDAC cells, highlighting a fundamental role of C1GALT1 in PDAC development. Note: This abstract was not presented at the meeting. Citation Format: Ting-Chun Kuo, Hsueh-Fen Juan, Yu-Wen Tien, Min-Chuan Huang. C1GALT1 activates multiple RTKs and promotes malignant behaviors in pancreatic adenocarcinoma cells [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 359. doi:10.1158/1538-7445.AM2017-359
Abstract 2385: Systematic characterization of kinase inhibitors reveals heterogeneity in responses by class and cell line
Authors: Caitlin E. Mills, Marc Hafner, Dejan Juric, Peter K. Sorger
Journal: Cancer Research (2017)

Abstract Several publications have addressed concerns surrounding drug response screens by pointing out sources of variability and by presenting recommendations for better experimental methods and more robust analytical approaches. In the presented profiling effort, we integrated the latest advances in drug response measurement and focused on data diversity and quality rather than on breadth. We selected 32 breast cancer cell lines with a strong bias towards triple negative lines as well as 4 cell lines established from relevant patient-derived xenografts. We evaluated a panel of clinically relevant kinase inhibitors using a microscopy-based drug response assay to measure drug potency, and to quantify drug efficacy in terms of growth inhibition (GR metrics) and cell death. The use of the GR metrics to quantify drug sensitivity enabled us to identify and study differences between cytostatic and cytotoxic responses. This systematic dose response dataset is complemented by measurements of baseline mRNA expression levels by RNAseq and endogenous protein levels by shotgun mass spectrometry across all cell lines. The completeness and controlled conditions under which these data sets were collected provide confidence in their integration. The baseline RNA and protein expression levels were used to build predictors of the measured drug responses with the goal of identifying the biological processes responsible for the differences in sensitivity across drugs and cell lines. Differences in the phenotypic responses of cell lines to kinase inhibitors with the same nominal targets have been investigated, and associated with variable inhibitor polypharmacology. Citation Format: Caitlin E. Mills, Marc Hafner, Dejan Juric, Peter K. Sorger. Systematic characterization of kinase inhibitors reveals heterogeneity in responses by class and cell line [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 2385. doi:10.1158/1538-7445.AM2017-2385
Abstract 3215: Therapeutic potential of dual-function small molecules for breast cancers
Authors: Nicole Nicholas, Alfredo Velena, Scott Grindrod, Mira Jung
Journal: Cancer Research (2017)

Abstract Epigenetic silencing of tumor suppressors is an important mechanism in tumor initiation and progression. A tumor suppressor gene, BRCA1, is part of complex molecules in the repair of DNA double-strand breaks (DSBs), and loss of BRCA1 contributes to both sporadic and inherited breast tumor progression. Furthermore, recent studies have shown that the ataxia-telangiectasia mutated (ATM) activity is abnormal in breast cancer. Therefore, we tested the hypothesis that the dual-functional drug that fused the HDAC inhibitor with an ATM activator may enhance killing of breast cancer (BC) cells by increasing ATM activation. In addition, the expression of ATM may enhance the synergistic antitumor effects of HDAC inhibitors in combination with radiotherapy. To determine the HDAC inhibitory potency, SP-1-303 was screened against a panel of Class I and Class II HDAC enzymes in vitro and identified as a pan-HDAC inhibitor (IC50=120 nM). Western blot confirmed that SP-1-303 increased acetylated histone H3/H4, α-tubulin, and phosphorylation of ATM within 30 min - 4 h in a time-dependent manner. Using two ER positive BC cell lines (MCF7 and T-47D), two triple negative breast cancer (TNBC) cell lines (MDA-MB-231 and HCC 1937), and one normal breast epithelial cell line as a control (MCF10A), the effects of SP-1-303 on cell growth and cell death were examined by performing cytotoxicity assays and flow cytometry. SAHA and Tamoxifen were used as controls. SP-1-303 conferred the values of cytotoxicity (IC50) for the ER positive BC cells in a range of 0.25-0.4 μM, while the values are in a range of 1-3 μM for TNBC and 12 μM for normal breast epithelial cells, respectively. Flow cytometry (FACS) analyses demonstrated significant increases in G1 arrest (81%) in MCF7 cells and a further enhancement in the G1 phase (91%) in combination with radiation. The data implies the mechanism of action from this drug—cancer cells are being arrested in the G1 phase of the cell cycle, a radiation sensitive phase, suggesting that SP-1-303 may have a synergistic effect with radiation on cell killing. Taken together, SP-1-303 had the largest impact on ER positive breast cancer over TNBC. These data imply that an increased cell death is occurring in ER positive breast cancers from these dual-action molecules through HDAC inhibition and increased ATM activation, suggesting that SP-1-303 alone or its combination with radiotherapy may improve clinical efficacy. Citation Format: Nicole Nicholas, Alfredo Velena, Scott Grindrod, Mira Jung. Therapeutic potential of dual-function small molecules for breast cancers [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 3215. doi:10.1158/1538-7445.AM2017-3215
Decoding Noncoding RNAs: Role of MicroRNAs and Long Noncoding RNAs in Ocular Neovascularization
Authors: Yan Zhang, Siwei Cai, Yurong Jia, Chen Qi, Jing Sun, Hong Zhang, Fei Wang, Yunshan Cao, Xiaorong Li
Journal: Theranostics (2017)

Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization.