tbuckley/cabot-search huggingface dataset:
Abstract 4591: Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL
Authors: Julia Boshuizen, Louise A. Koopman, Esther C. Breij, David Satijn, Daniel Peeper, Paul W. Parren
Journal: Cancer Research (2017)

Abstract Upon therapeutic pressure, cancers commonly select for drug-resistant, invasive subpopulations with elevated expression of the receptor tyrosine kinase AXL. Besides the correlation between high AXL expression and induction of epithelial-to-mesenchymal transition, a process known to support metastasis, ample evidence also links AXL to resistance against a variety of targeted therapies, including inhibitors of the MAPK pathway in malignant melanoma and the EGFR pathway in lung cancer. AXL-107-MMAE (HuMax-AXL-ADC) is a therapeutic antibody-drug conjugate specific for AXL, containing the microtubule disrupting agent monomethyl auristatin E as the cytotoxic payload. AXL-107-MMAE was previously shown to induce potent cytotoxicity in vitro and in vivo, which was dependent expression of AXL on the cell surface. We evaluated the capacity of AXL-107-MMAE to target AXL-positive MAPK pathway inhibitor resistant tumor cells, using malignant melanoma as a clinically relevant example. First, AXL-107-MMAE was shown to induce cytotoxicity in BRAF-mutant tumor cell lines that showed AXL expression upon acquired resistance to BRAF-inhibitors. In contrast, no cytotoxicity was observed in the BRAF-inhibitor-sensitive, AXL-negative parental cell lines. In heterogeneous tumor cell cultures, treatment with a BRAF-inhibitor selected for AXL-high, MAPK pathway inhibitor-insensitive melanoma cells, which was prevented by combined BRAF-inhibitor and AXL-107-MMAE treatment. Interestingly, we observed marked AXL upregulation in biopsies obtained from patients after they developed resistance to MAPK pathway inhibitors compared to paired pre-treatment biopsies. The in vivo potential of AXL-107-MMAE in malignant melanoma was demonstrated using BRAFV600E-mutated xenograft model derived from a patient who developed resistance to the BRAF inhibitor vemurafenib in the clinic. This indicates that AXL expression levels in treatment-resistant malignant melanoma are sufficient to induce tumor regression with AXL-107-MMAE, at least in this model system. These findings merit clinical validation of the targeting of both treatment-naïve and drug-resistant cancers with AXL-107-MMAE, either alone or in combination with other targeted therapies. Citation Format: Julia Boshuizen, Louise A. Koopman, Esther C. Breij, David Satijn, Daniel Peeper, Paul W. Parren. Specific elimination of invasive and multidrug-resistant cancer cells by an antibody-drug conjugate targeting AXL [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 4591. doi:10.1158/1538-7445.AM2017-4591
Abstract 928: Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem cells
Authors: Amira S. Fyala, Ahmed S. Sultan
Journal: Cancer Research (2017)

Abstract Manuka honey is well known for its anti-bacterial and wound healing properties but its anticancer role against cancer stem cells (CSC) in hepatocellular carcinoma (HCC) cell lines and the underlying molecular mechanisms remain uninvestigated. Recently, we identified a CSC subpopulation in HCC cell lines characterized by their CD133+ and CD90+ phenotype. The CD133+/ CD90+cells demonstrated a more aggressive phenotype than the CD133-/ CD90- counterpart and formed metastatic lesions in the lung of immunodeficient mice. In order to evaluate the effect of Manuka honey alone or in combined treatment with Metformin, a biguanide that has been widely used to treat type 2 diabetes, on cell viability and apoptosis induction in human HCC cell lines, isolated and identified CD133+/ CD90+subpopulation CSC were used. Cell viability was monitored using an MTT assay. In addition, apoptosis induction was labeled by Annexin V-fluorescein isothiocyanate/propidium iodide and measured using flow cytometry. Western blotting was used to examine the protein expression of p53, Bcl-2, Bax, Bcl-2-associated death promoter (Bad), Bcl-2 homologous antagonist/killer (Bak) and cleaved-caspases-3 and -9. The results of the present study revealed that Manuka honey alone or in combined treatment with Metformin suppressed the cell viability of CD133+/CD90+cells in a concentration-dependent manner and the maximum effect was detected in combined treatment after 24 h. In addition, Manuka honey alone or in combined treatment with Metformin induced a significant apoptosis in the tested cells. Furthermore, it was demonstrated that combined treatment increased the expression of proapoptotic proteins, including p53, Bax, Bad and Bak, while it decreased the protein level of antiapoptotic protein Bcl-2 compared to control, Manuka honey or Metformin alone. Furthermore, the combined treatment strongly inhibited stemness characteristics of CSC subpopulation, colony formation and dramatically inhibited CD133+/CD90+tumor growth in vivo. Our data demonstrated that combined treatment induced apoptosis in CD133+/CD90+ subpopulation through G1 arrest in the cell-cycle and regulating p53/Bcl-2/caspase-3 signaling pathway. In conclusion, our results suggested that Monuka honey alone or combined treatment with Metformin may be a potential treatment for apoptosis induction in CSC and may provide a novel therapeutic model for HCC. Citation Format: Amira S. Fyala, Ahmed S. Sultan. Combined treatment by manuka honey and metformin inhibited growth and inducted apoptosis in CD133+and CD90+ subpopulation hepatocellular carcinoma cancer stem 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 928. doi:10.1158/1538-7445.AM2017-928
Abstract 2739: Low-pass whole genome sequencing detects copy number variations in circulating tumor DNA
Authors: Xiaoji Chen, Jill M. Spoerke, Kathryn Yoh, Walter C. Darbonne, Ling-Yuh Huw, Steven Gendreau, Shih-Min A. Huang, Mark R. Lackner
Journal: Cancer Research (2017)

Abstract Circulating tumor DNA (ctDNA) is released from necrotic/apoptotic tumor cells into the bloodstream. Recent studies have demonstrated the value of using ctDNA as biomarkers in cancer diagnosis, prognosis, and drug resistance. Unlike local tissue biopsy, ctDNA collection and analysis is non-invasive, allows continuous monitoring of clonal evolution, and provides an overview of tumor heterogeneity. Copy number variations (CNVs) play an important role in cancer biology. However, traditional CNV analyses of ctDNA using droplet digital PCR (ddPCR) and SNP arrays can only assess a small number of genes due to the low abundance of ctDNA in the majority of patient samples. Next generation sequencing (NGS) offers a more efficient and high-throughput way to study CNVs in ctDNA. Here, we evaluated the use of low-pass whole genome sequencing (WGS) in determining CNVs in ctDNA. In this work, cell-free DNA was isolated from 1-5 ml of plasma from phase II clinical trial patients with metastatic breast cancer and non-small cell lung cancer (NSCLC) using the QIAamp Circulating Nucleic Acid Kit (QIAGEN). DNA yield was determined by ddPCR, with a range from 2-4000 ng. Sequencing libraries were prepared using 2-10 ng DNA by the ThruPLEX Plasma-Seq Kit (Rubicon Genomics). WGS at 0.1x, 0.25x, 0.5x, and 1x coverage was performed on Illumina NextSeq, and data was analyzed using Nexus Copy Number software (BioDiscovery). As a reference, we sequenced DNA from peripheral blood mononuclear cells (PBMCs) of 20 healthy donors at the same coverage. Low-pass WGS was also performed on a subset of matched tumor tissue samples as comparisons. Our results showed that WGS of ctDNA at 0.5x coverage was efficient to identify CNVs. CNVs were detected in ctDNA from about half of the patients analyzed, and in general CNVs identified in ctDNA matched the ones found in tumor tissue from the same patient. We also found that CNV patterns from different time points of the same patients clustered together. With this promising system, we will present CNV analysis in ctDNA from breast cancer and NSCLC patients enrolled in phase II clinical trials of the PI3K inhibitor pictilisib. We will evaluate the ability of the method to classify patients into different subgroups, monitor tumor progression, and identify drug resistance mechanisms. Citation Format: Xiaoji Chen, Jill M. Spoerke, Kathryn Yoh, Walter C. Darbonne, Ling-Yuh Huw, Steven Gendreau, Shih-Min A. Huang, Mark R. Lackner. Low-pass whole genome sequencing detects copy number variations in circulating tumor DNA [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 2739. doi:10.1158/1538-7445.AM2017-2739
Abstract 4422: Capsaicin suppresses pancreatic tumor growth by inhibiting tumor cell metabolism
Authors: Sharavan Ramachandran, Sanjay K. Srivastava
Journal: Cancer Research (2017)

Abstract Tumor cell metabolism is considered to be a hallmark of tumorigenic progression. Pancreatic cancer cells are shown to develop addiction towards the metabolic pathways like glycolysis and mitochondrial respiration to meet energy demands. Pancreatic tumor cells predominantly utilize cytosolic aerobic glycolysis for energy production. In our previous studies, we have reported that capsaicin treatment inhibits the survival of AsPC-1 and BxPC-3 pancreatic cancer cell lines. In this study, we evaluated the effect of capsaicin on glycolysis and mitochondrial respiration in pancreatic cancer cells. Our results showed that capsaicin treatment reduced the extra-cellular acidification rate (glycolysis) and oxygen consumption rate (mitochondrial respiration) in AsPC-1 and BxPC-3 cells in a concentration-dependent manner after 24h of treatment. Capsaicin treatment caused 86% and 55% down-regulation of glycolysis process in AsPC-1and BxPC-3 cells respectively. Our results also indicate the inhibition of glycolytic capacity and glycolytic reserve by capsaicin treatment indicating the potential of capsaicin to inhibit glycolysis. In addition, capsaicin treatment reduced 98% of basal oxygen consumption rate and ATP production in AsPC-1 cells. Furthermore, capsaicin treatment inhibited spare respiratory capacity &amp; proton leak in a concentration dependent manner in AsPC-1 cells. Treatment of AsPC-1 and BxPC-3 with capsaicin for 48h also inhibited the expression of LDH-A and its upstream regulators such as HIF-1α, pSTAT3 (Y705) and EGFR as evaluated by Western blot. Our study thus indicate that capsaicin suppresses pancreatic tumor growth by down-regulating glycolysis and mitochondrial respiration. Further mechanistic studies are in progress. [Supported in part by R01 grant CA129038, awarded to (S.K.S.) by the National Cancer Institute]. Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Capsaicin suppresses pancreatic tumor growth by inhibiting tumor cell metabolism [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 4422. doi:10.1158/1538-7445.AM2017-4422
Right idea, wrong magnitude system
Authors: Stella F Lourenco, Lauren S Aulet, Vladislav Ayzenberg, Chi-Ngai Cheung, Kevin J Holmes
Journal: Behavioral and Brain Sciences (2017)

Leibovich et al. claim that number representations are non-existent early in life and that the associations between number and continuous magnitudes reside in stimulus confounds. We challenge both claims - positing, instead, that number is represented independently of continuous magnitudes already in infancy, but is nonetheless more deeply connected to other magnitudes through adulthood than acknowledged by the "sense of magnitude" theory.
Abstract 458: Choline metabolism in cancer cells modifies PD-L1 expression
Authors: Balaji Krishnamachary, Marie-France Penet, Yelena Mironchik, Zaver M. Bhujwalla
Journal: Cancer Research (2017)

Abstract Increased expression of choline kinase-α (Chk-α), the enzyme that converts choline to phosphocholine has been observed in most cancer cells including breast (1). This increase of choline kinase results in increased production of phosphocholine that is used in the synthesis of membrane phosphatidylcholine. We investigated the relationship between Chk-α and the programmed death ligand-1 (PD-L1) expression in triple negative MDA-MB-231 human breast cancer cells. Expression of PD-L1 in response to the secretion of interferon gamma (IFNγ) by cytotoxic T cells and its binding to the immune checkpoint PD-1 on T cells results in cancer cells escaping destruction by the immune system (2). Quantitative real-time PCR analysis (q-RT-PCR) did not reveal any change in PD-L1 mRNA expression between MDA-MB-231 expressing an empty vector control plasmid (231-EV) and MDA-MB-23 stably expressing shRNA against Chk (231-Chk). However, there was a difference in the mean intensity fluorescence (MIF) between 231-EV (325 ±11.5, n=2) and 231-Chk (527±18.5, n=2) in the FACS analysis. Upon induction with IFNγ (10ng/ml) for 24h, there was 1.23 fold increase in PD-L1 mRNA in 231-Chk compared to 231-EV. Interestingly, the MIP for cell surface expression of PD-L1 was 600±21 (n=2) for 231-EV compared to 872±16 (n=2) for 231-Chk cells. Values represent mean + SE. These data suggest that the cell surface increase of PD-L1 in 231-Chk cells could be due to translocation. Increased PD-L1 expression creates an opportunity to deliver PD-L1 targeted nanoparticles carrying therapeutic cargo. Since most conventional treatments result in a decrease of Chk-α and phosphocholine, our data suggest that these treatments may also result in cancer cells escaping immune surveillance through expression of PD-L1. Acknowledgements: This work was supported by NIH R01CA136576 and P50 CA103175. Reference: 1) Glunde K et al, Cancer Res 65, 11034 (2005)., 2) Zou W, Chen L, Nat Rev Immunol 8(6), 467-77 (2008). Citation Format: Balaji Krishnamachary, Marie-France Penet, Yelena Mironchik, Zaver M. Bhujwalla. Choline metabolism in cancer cells modifies PD-L1 expression [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 458. doi:10.1158/1538-7445.AM2017-458
Abstract 3570: Germline structural variant detection with variation graphs
Authors: Eric T. Dawson, Erik Garrison, Adam Novak, Benedict Paten, Jordan Eizinga, Glenn Hickey, Stephen Chanock, Richard Durbin
Journal: Cancer Research (2017)

Abstract Structural variants play a major role in many cancers. However, classical methods of detection rely on searching for mapping signatures and a perpetual “rediscovering” of variants relative to the reference. A more efficient technique would be to map directly against known variants. We present a novel method for detecting known structural variants in next-generation sequencing data using variation graphs. Variation graphs are reference-like structures that succinctly encode the variation present within a population. Existing tools enable reads to be efficiently mapped against this graph structure. We are able to speed up queries for the presence or absence of variants by reducing the operation to a simple lookup in an external index. The current implementation of our variation graph approach is open source and publically available as part of the variation graph toolkit (https://github.com/vgteam/vg). Our method of variant typing on variation graphs has great potential to model and assess the complexity of cancer genomes while remaining efficient enough to make analysis tractable. Citation Format: Eric T. Dawson, Erik Garrison, Adam Novak, Benedict Paten, Jordan Eizinga, Glenn Hickey, Stephen Chanock, Richard Durbin. Germline structural variant detection with variation graphs [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 3570. doi:10.1158/1538-7445.AM2017-3570
Abstract 5719: Long intergenic non-coding RNAs: a new independent risk predictors in multiple myeloma
Authors: Mehmet K. Samur, Annamaria Gulla, Mariateresa Fulciniti, Anil Aktas Samur, Raphael Szalat, Masood Shamas, Florence Magrangeas, Stephane Minvielle, Kenneth Anderson, Giovanni Parmigiani, Hervé Avet-Loiseau, Nikhil Munshi
Journal: Cancer Research (2017)

Abstract RNA has diverse sets of regulatory functions and a recent analysis of RNA repertoire has identified a large numbers of non-coding transcripts. One of which, long intergenic non-coding RNA (lincRNA) with transcripts longer than 200 nucleotides, are located between the protein coding genes and do not overlap exons of either protein-coding or other non-lincRNA genes. lincRNAs have been considered to provide regulatory functions, however, their precise role in cellular biology remains unclear. Here, we have studied lincRNAs using uniformly treated patients to show their impact on survival outcome in MM. We performed RNA-seq on CD138+ MM cells from 360 newly-diagnosed patients and 18 normal plasma cells (NPM) and analyzed for lincRNA and protein coding genes. MM patient data for clinical characteristics, cytogenetic and FISH as well as clinical survival outcomes were also analyzed and correlated with lincRNA data. Our data showed expression of 951 lincRNAs (median TPM &amp;gt; 1) with 351 lincRNAs differentially expressed between MM and normal plasma cells. Using only the expressed lincRNAs, we applied log rank tests for quartile 1 (Q1) versus Q2 through Q4 and Q4 versus Q1 through Q3 in order to identify under- and overexpressed prognostic genes, respectively. Four under and seven overexpressed genes were selected for final model. We used Más-o-menos for final predictive model, which simply calculates the risk score, by using expression values. The Kaplan-Meier estimates of EFS at 4 years were 53.3% (95% CI, 45.1% to 63.1%) and 32.6% (95% CI, 25.1% to 42.2%), and OS at 4 years were 93.2% (95% CI, 88.9% to 97.6%) and 71.1% (95% CI, 62.9% to 80.3%) in our patients having a low or high risk score. When applied to patient cohort separated by other risk categorization including minimal residual disease status (MRD), cytogenetic risk status (del17p, t(4;14) and t(14;16)) and International Staging System (ISS), lincRNA signature was able to further identify patients with significant differential survival outcomes. In summary, we report that lincRNAs have an independent effect on survival outcome in MM and provides rational for its use in risk stratification as well as to understand biological impact. Citation Format: Mehmet K. Samur, Annamaria Gulla, Mariateresa Fulciniti, Anil Aktas Samur, Raphael Szalat, Masood Shamas, Florence Magrangeas, Stephane Minvielle, Kenneth Anderson, Giovanni Parmigiani, Hervé Avet-Loiseau, Nikhil Munshi. Long intergenic non-coding RNAs: a new independent risk predictors in multiple myeloma [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 5719. doi:10.1158/1538-7445.AM2017-5719
Abstract 865: Cytoplasmic polyadenylation element binding protein 2 splice variants have opposing functions in the epithelial to mesenchymal transition pathway
Authors: James T. DeLigio, Charles E. Chalfant, Margaret A. Park
Journal: Cancer Research (2017)

Abstract Alternative splicing of cytoplasmic polyadenylation element binding protein 2 (CPEB2) generates two isoforms, CPEB2B and CPEB2A, through inclusion/exclusion of exon 4, respectively, in mature mRNA. We previously reported that CPEB2B is essential to establish anoikis resistance (AnR), and promotes metastasis using in vivo orthotopic models. In contrast, CPEB2A decreases AnR and metastatic transformation. In the current studies, we examined the function of CPEB2 isoforms using next generation sequencing analysis of downstream signaling pathways. We found that CPEB2B expression upregulated AnR in breast cancer cells and induced key genes/proteins in the epithelial to mesenchymal transition (EMT) and hypoxic response (hypoxia inducible factor 1α (HIF1α)-dependent) pathways. Inhibition of either TWIST1 or HIF1α reduced the CPEB2B-mediated AnR in cells ectopically expressing CPEB2B, confirming a link between CPEB2 alternative splicing and the induction of the EMT/hypoxia pathways. We then extended our findings, and demonstrated that CPEB2 alternative splicing induced de novo translation of both HIF1α and TWIST1, whereas CPEB2A decreased translation of these factors. Furthermore, CPEB2 isoforms were found to modulate differential polyadenylation site selection of the TWIST1 3’UTR and competed for binding to HIF1α and TWIST1 3’UTR cytoplasmic polyadenylation element (CPE) site sequences. These results demonstrate that CPEB2A and CPEB2B modulate the translation of factors in the EMT/hypoxia pathways in an opposing fashion via differential polyadenylation site selection and subsequent translation. Citation Format: James T. DeLigio, Charles E. Chalfant, Margaret A. Park. Cytoplasmic polyadenylation element binding protein 2 splice variants have opposing functions in the epithelial to mesenchymal transition pathway [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 865. doi:10.1158/1538-7445.AM2017-865