bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B26: RRx-001, a novel epigenetic modulator: Resensitization to previously failed therapy in the ongoing phase 2 colorectal cancer study, ROCKET
Authors: Reid Tony , Fisher George , Carter Corey , Cho-Phan Cheryl , Kunz Pamela , Oronsky Bryan , Fanger Gary , Stirn Meaghan , Caroen Scott , Parker Christopher , Scicinski Jan 
Published: May 2016

Abstract
Background: The development of resistance to chemotherapies in cancer leads to disease progression resulting in impaired survival. Resensitization to these previously effective but now failed therapies could lead to improvements in patient survival and response. RRx-001, a novel dinitroazetidine ROS-mediated epigenetic modulator that has demonstrated activity against DNMTs and HDACs may resensitize colorectal cancer patients to previously effective irinotecan therapies resulting in improvements in survival.
Methods: The ROCKET study is a two stage trial that investigates RRx-001-mediated resensitization to irinotecan therapies. Patients with metastatic colorectal cancer who previously responded, then progressed on irinotecan-based therapies, with or without bevacizumab, cetuximab or panitumumab and an ECOG PS 0-1 are randomized in Stage 1 to receive RRx-001 1xweek or regorafenib until progression or unacceptable toxicity. Patients then advance to Stage 2 to receive irinotecan-based therapies. Target accrual is approx. 190 patients and the primary endpoint is overall survival with secondary endpoints to investigate resensitization. Recruitment is ongoing.
Study Status and Results: To date, 28 patients have been randomized with 20 entering the resensitization stage of the study. 13 post RRx-001 patients entered the second stage of the study showing an improving patient survival, marked decreases in CEA and radiological responses. In contrast, the 7 regorafenib patients eligible for stage 2 were too systemically unwell to proceed to subsequent treatment.
Conclusions: Early results suggest that RRx-001, a systemically non-toxic epigenetic agent, may resensitize colorectal cancer patients to irinotecan-based therapies. These interesting early results appear to be generalized and may translate to increased overall survival, adding an additional regimen after disease progression. The trial is continuing.
Citation Format: Tony Reid, George Fisher, Corey Carter, Cheryl Cho-Phan, Pamela Kunz, Bryan Oronsky, Gary Fanger, Meaghan Stirn, Scott Caroen, Christopher Parker, Jan Scicinski. RRx-001, a novel epigenetic modulator: Resensitization to previously failed therapy in the ongoing phase 2 colorectal cancer study, ROCKET. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B26.
Abstract B28: BET bromodomain inhibitors antagonize Brd4-Mediator complexes to undermine the acute myeloid leukemia cell state
Authors: Bhagwat Anand S. , Roe Jae-Seok , Mok Beverly A. , Vakoc Christopher R. 
Published: May 2016

Abstract
Acute myeloid leukemia (AML) is a hematologic malignancy with a 5-year survival rate of under 30%. We recently identified the bromodomain and extraterminal (BET) protein Brd4 as a therapeutic target in AML, and several trials are currently evaluating the clinical utility of BET inhibitors for this disease. BET inhibitors displace Brd4 from chromatin and subsequently reduce the expression of key oncogenes, such as Myc, leading to AML blast differentiation and cell death. However, the mechanism by which Brd4 maintains oncogene expression in AML is still unclear. We hypothesized that Brd4 functions by working with other coactivators in AML to promote expression of oncogenes. One such coactivator is the Mediator complex, which is comprised of ~30 subunits and directly contacts RNA Polymerase II to regulate its function. Initial purifications of Mediator from mammalian cells identified Brd4 as an associated factor. Using ChIP-seq analysis in AML cells, we show that Brd4 and Mediator closely co-localize across the genome. Moreover, chemical inhibition of Brd4 results in the displacement of Mediator from enhancer and promoter regions across the genome, an effect that occurrs within 30 minutes of treatment. While the genome-wide loss of Mediator occupancy is approximately 2-fold, a subset of promoters and enhancers exhibit dramatic loss of Mediator occupancy. Importantly, these regions are disproportionately associated with genes related to leukemia biology but only modestly overlap with super-enhancers. In addition, we show that shRNA-based knockdown of several Mediator subunits phenocopies the transcriptional and cellular effects of Brd4 inhibition without affecting levels of Brd4 in the cell. These effects include downregulation of Myc expression, induction of myeloid differentiation, and reduction of P-TEFb recruitment to chromatin. These findings support a model in which Brd4 functions in concert with the Mediator complex to maintain oncogenic gene expression programs in leukemia and shed light on the mechanisms of action underlying a promising new class of therapeutics for AML.
Citation Format: Anand S. Bhagwat, Jae-Seok Roe, Beverly A. Mok, Christopher R. Vakoc. BET bromodomain inhibitors antagonize Brd4-Mediator complexes to undermine the acute myeloid leukemia cell state. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B28.
Abstract B31: EZH2 suppresses the interferon-stimulated gene response in non-Hodgkin lymphoma
Authors: Bradley William D. , Yuan Chih-Chi , Zhao Feng , Lee Christina , Williamson Kaylyn E. , Arora Shilpi , Hatton Charlie , Bryant Barbara M. , Trojer Patrick 
Published: May 2016

Abstract
Pharmacological inhibition of the histone lysine methyltransferase EZH2 has emerged as a therapeutic strategy for the treatment of non-Hodgkin Lymphoma (NHL), in particular for cases with mono-allelic mutations in the EZH2 catalytic domain. Potent, selective EZH2 small molecule inhibitors have achieved tumor regression in mutant EZH2-containing preclinical lymphoma models and several of these inhibitors are currently engaged in cancer-focused clinical trials. Here, we show that the presence of EZH2 mutations do not always confer EZH2 inhibitor sensitivity. We discovered that EZH2 is usurped by lymphoma cells to attenuate JAK/STAT signaling and to repress pro-apoptotic interferon response genes. EZH2 inhibition results in the broad induction of interferon-stimulated genes (ISGs) in several phenotypically sensitive NHL cell models. In mutant EZH2-containing insensitive models, EZH2 inhibitors synergize specifically with type I interferons (IFNs) in vitro and in vivo to induce ISGs and apoptosis. The profound combinatorial activity of EZH2 inhibitors and type I IFNs is not restricted to NHL models with mutant EZH2 and, is preferentially observed in models that are not affected by either single agent. Molecular consequences of EZH2 inhibitor and type I IFN combinatorial treatment include STAT1 activation, binding of STAT transcription factor complexes to ISGs, reduction of H3K27me3 levels and increase of H3K4me3 levels at ISG transcriptional start sites, and ISG transcriptional activation. The molecular and anti-proliferative effects of the combination can be suppressed by inactivation of the JAK/STAT signaling pathway, by using the JAK inhibitor ruxolitinib. We suggest that EZH2 inhibitors can be therapeutically combined with type I IFNs for the treatment of NHL.
Citation Format: William D. Bradley, Chih-Chi Yuan, Feng Zhao, Christina Lee, Kaylyn E. Williamson, Shilpi Arora, Charlie Hatton, Barbara M. Bryant, Patrick Trojer. EZH2 suppresses the interferon-stimulated gene response in non-Hodgkin lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B31.
Abstract B32: Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses
Authors: Chiappinelli Katherine B. , Strissel Pamela L. , Desrichard Alexis , Li Huili , Henke Christine , Akman Benjamin , Hein Alexander , Rote Neal S. , Cope Leslie M. , Snyder Alexandra , Makarov Vladimir , Budhu Sadna , Wolchok Jedd , Zahnow Cynthia A. , Mergoub Taha , Chan Timothy A. , Strick Reiner , Baylin Stephen B. 
Published: May 2016

Abstract
DNA methyltransferase inhibitors (DNMTis) upregulate immune attraction, including the interferon response, in solid tumors. We now define viral defense signaling as one mechanism for this. In epithelial ovarian cancer cells DNMTis upregulate viral defense by cytosolic sensing of double-stranded RNA (dsRNA), triggering a Type I Interferon response, upregulation of downstream interferon response genes, and increased apoptosis. Knockdown of the dsRNA sensors TLR3 and MAVS and inhibition of the interferon alpha/beta receptor blunt the DNMTi induced dsRNA response. DNMTis cause apoptosis of cancer cells, which is partially rescued by inhibiting the interferon alpha/beta receptor. We observe upregulation and demethylation of hypermethylated endogenous retroviruses (ERVs) and overexpression of individual ERVs whose sense and anti-sense transcripts may be key candidates for triggering the above signaling. Overexpression of ERVs alone is sufficient to trigger an interferon response in the absence of DNMTis. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and basal expression of the viral defense signature separates primary TCGA samples for multiple tumor types into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model. We thus define a major mechanism for how DNMTis may induce cancer cells to increase immune attraction and possibly sensitize patients to immunotherapy. Experiments determining which Aza-upregulated molecules on tumor cells are necessary for attraction and activation of host immune cells are ongoing.
Citation Format: Katherine B. Chiappinelli, Pamela L. Strissel, Alexis Desrichard, Huili Li, Christine Henke, Benjamin Akman, Alexander Hein, Neal S. Rote, Leslie M. Cope, Alexandra Snyder, Vladimir Makarov, Sadna Budhu, Jedd Wolchok, Cynthia A. Zahnow, Taha Mergoub, Timothy A. Chan, Reiner Strick, Stephen B. Baylin. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr B32.
Abstract IA09: Nucleosome barriers to transcription
Authors: Henikoff Steven , Weber Christopher M. , Teves Sheila S. , Ramachandran Srinivas 
Published: May 2016

Abstract
Nucleosomes are barriers to transcription in vitro, but is this the case in vivo? To address this question, we have introduced a simple and general method to comprehensively map the positions of elongating and arrested RNA polymerase II (RNAPII) at nucleotide resolution. We find that the nucleosomes are barriers to RNAPII elongation at essentially all genes, with the +1 nucleosome downstream of the transcriptional start site the strongest barrier. Depletion of the histone variant H2A.Z from a nucleosome strengthens the barrier to RNAPII, which suggests that H2A.Z has evolved to reduce nucleosome barrier strength. One potential mechanism for overcoming the nucleosome barrier to transcription is the DNA torsional stress created by RNA polymerase transit, which can unwrap and destabilize nucleosomes. We find that inhibiting topoisomerases results in both increased torsion measured at high resolution and increased turnover of nucleosomes, confirming this mechanism in vivo. We have also applied H4S47C-anchored cleavage mapping to identify non-canonical nucleosomes, leading to the characterization of chromatin remodeling intermediates at a subset of +1 nucleosome positions.
Citation Format: Steven Henikoff, Christopher M. Weber, Sheila S. Teves, Srinivas Ramachandran. Nucleosome barriers to transcription. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA09.
Abstract IA18: Functional characterization of the tumor suppressor lysine-specific methyltransferase KMT2D in lymphoma
Authors: Ortega-Molina Ana , Boss Isaac W. , Canela Andres , Pan Heng , Jiang Yanwen , Zhao Chunying , Jiang Man , Hu Deqing , Lee Ji-Eun , Chen Hua-Tang , Ennishi Daisuke , Scott David W. , Hother Christoffer , Liu Shichong , Cao Xing-Jun , Tam Wayne , Shaknovich Rita , Garcia Benjamin A. , Gascoyne Randy D. , Ge Kai , Shilatifard Ali , Elemento Olivier , Nussenzweig Andre , Melnick Ari M. , Wendel Hans-Guido 
Published: May 2016

Abstract
Genomic studies have revealed surprising new insights into the genetics of human B-cell lymphomas. Of particular note the lysine-specific methyl transferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma (FL) and in diffuse large B-cell lymphoma (DLBCL). However, the biological consequences of KMT2D mutations in lymphoma are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and promotes lymphoma development in vivo. Integrative analyses of KMT2D function indicate specific and focal effects on H3K4 methylation and gene expression. These include B-cell growth and differentiation signals such as the CD40, JAK/STAT, and B-cell receptor pathways. Moreover, KMT2D targets include frequently mutated tumor suppressor genes such as TNFAIP3/A20, SOCS3, and TNFRSF14/HVEM. In this manner, KMT2D deficiency disrupts the physiological process of B-cell differentiation, facilitates malignant outgrowth, and can impede therapies acting on the CD40 and B-cell receptor pathways.
Citation Format: Ana Ortega-Molina, Isaac W. Boss, Andres Canela, Heng Pan, Yanwen Jiang, Chunying Zhao, Man Jiang, Deqing Hu, Ji-Eun Lee, Hua-Tang Chen, Daisuke Ennishi, David W. Scott, Christoffer Hother, Shichong Liu, Xing-Jun Cao, Wayne Tam, Rita Shaknovich, Benjamin A. Garcia, Randy D. Gascoyne, Kai Ge, Ali Shilatifard, Olivier Elemento, Andre Nussenzweig, Ari M. Melnick, Hans-Guido Wendel. Functional characterization of the tumor suppressor lysine-specific methyltransferase KMT2D in lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA18.
Abstract B1-06: Tumor genotyping using full cloud based pipeline
Authors: Ueda Hiroki , Yamamoto Shogo , Aburatani Hiroyuki 
Published: May 2016

Abstract
With emergence of Next Generation Sequencer (NGS), data processing using cloud computing and parallel computation becomes necessary. To process huge NGS data, especially yielded from illumina Hiseq2000 sequencer, we have developed a Hadoop/Spark based mapping soft “Volt” which used spaced hash index and Smith-Waterman algorithm with comparable speed and accuracy to existing NGS mapping software. This software can run both on standalone environment and Hadoop/Spark environment, and in later case, the software is directory integrated using Hadoop API and can read and write data to Hadoop Distributed File System (HDFS), and mapping process is distributed using MapReduce framework. To speedup mapping speed, the software uses two seeds match for near perfect hit, and uses full length seed hit for mismatched hit. Also, we have developed tumor genotyper “karkinos” which detects single nucleotide variation (SNV), copy number variation (CNV), calculate tumor cellularity simultaneously. In this genotyper, we proposed “Open genotyper format”, by using that, each heuristic filtering algorithm can be implemented by add on style development. We integrated software into one analysis pipeline and tested on large cohort of liver cancer data. Detailed algorithm and performance data will be shown at the meeting.
Citation Format: Hiroki Ueda, Shogo Yamamoto, Hiroyuki Aburatani. Tumor genotyping using full cloud based pipeline. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-06.
Abstract B1-08: Deep learning for the large-scale cancer data analysis
Authors: Tsuji Shingo , Aburatani Hiroyuki 
Published: May 2016

Abstract
The advanced cancer research fields have been producing vast amount of multi-omics data in various cancer types, and the most of the data are publicly available. It is unquestionably important to analyze these data with unbiased and generalized methodology for obtaining the deeper insights into cancer biology.
Machine learning algorithms, such as k-means clustering, Support Vector Machines (SVM), and Random Forests (RF), have been applied to biological data analysis including cancer research. In this area, deep learning is gaining attention due to its high performance and generalized characteristics for analyzing complex data.
To explore the possibilities for applying deep learning algorithms to the cancer multi-omics data analysis, we compared the performance among SVM, RF, and deep learning. We build the models for predicting cancer types of TCGA pan-cancer data set, and confirmed the advantages for deep learning.
When we applied the algorithm to multi-omics data such as gene expression, DNA methylation, and somatic mutations, the input nodes of the neural network represented each data type. Autoencoders, components of the deep learning models, involve the weighted relationships among the input nodes, therefore we can find the unknown dependencies of some nodes by analyzing the networks of the model.
The results suggested that the deep learning architecture would be promising methodology to progress the cancer research in the data explosion era.
Citation Format: Shingo Tsuji, Hiroyuki Aburatani. Deep learning for the large-scale cancer data analysis. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-08.
Abstract B1-11: Application of the CN-AVG method to reconstruct the evolutionary history of glioblastoma multiforme
Authors: Ballinger Tracy J. , Zerbino Daniel , Paten Benedict , Haussler David 
Published: May 2016

Abstract
We have constructed evolutionary histories of cancer genomes using a new method, the Copy Number Ancestral Variation Graph (CN-AVG). Unlike previous cancer evolutionary studies which infer the clonal structure and evolutionary history of a tumor using single nucleotide variant frequencies, the CN-AVG method predicts the ordering of structural rearrangements, such as inversions, duplications, and deletions, using copy number changes and breakpoints derived from whole genome sequencing data. Because finding the most parsimonious ordering of genomic rearrangements is an NP hard problem, we build a consensus history by merging a large number of possible evolutionary histories generated from MCMC sampling. We tested the CN-AVG method on simulated rearranged genomes and achieved an average accuracy of 62%. We also found that accuracy decreased with increasing complexity of the simulated rearrangements, as expected. We then applied the method to TCGA Glioblastoma Multiforme genomes to search for evolutionary patterns in this disease. The CN-AVG method may distinguish driver mutations as the early rearrangement events and passenger or secondary mutations as the later events in the reconstructed evolutionary history of the tumor, and will be powerful for both the clinic and for research.
Citation Format: Tracy J. Ballinger, Daniel Zerbino, Benedict Paten, David Haussler. Application of the CN-AVG method to reconstruct the evolutionary history of glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-11.
Abstract B1-18: Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model
Authors: Tseng Alan , Li Wanda , Lee Kim-Chung , Yung Karrie , Lam Ching-Wan , Mak Tak 
Published: May 2016

Abstract
Isocitrate dehydrogenase 1 (IDH1) mutations are common drivers of acute myeloid leukemia (AML). While mutant IDH1 is known to disrupt DNA methylation, gene expression, and metabolism in cell lines, it is not known how mutant IDH1 alters global metabolism in vivo. The purpose of this study is to find differential enzymes and metabolites in IDH1 wild type versus mutant AML and knock in mice by integrating differential genes and metabolites in a metabolic network.
Differential genes were found by comparing gene expression and DNA methylation in IDH1 mutant (n = 12) and wild type (n = 89) cytogenetically normal AML patients from The Cancer Genome Atlas. Differential metabolites were found by untargeted liquid chromatography-mass spectrometry of urine, plasma, and bone marrow hematopoietic stem and progenitor cells from unpaired 1-2 year old mixed-sex IDH1 myeloid knock in (n = 13) and control mice (n = 14). Integrative analysis was performed using the MetScape 2 Cytoscape plugin.
71 differential genes and 52 differential metabolites were mapped to the global metabolic network. The set of differential genes and metabolites formed 10 connected subnetworks containing reactions in sphingolipid, phospholipid, and bile acid metabolism. Two enzymes in the subnetworks were differentially expressed in an independent IDH1 mutant versus wild type AML dataset: acyl-CoA thioesterase 4 (ACOT4) and galactosylceramidase (GALC) (P &lt; 0.05, false discovery rate ≤ 0.3). ACOT4 and GALC were significantly upregulated (P &lt; 0.02) in acute promyelocytic leukemia cells treated with all-trans retinoic acid.
In conclusion, we have found novel differential genes and metabolites in IDH1 mutant systems which may be relevant to leukemia differentiation treatment. Integrative analysis of gene expression and metabolite levels could be useful for finding dysregulated metabolic subnetworks in cancer.
Citation Format: Alan Tseng, Wanda Li, Kim-Chung Lee, Karrie Yung, Ching-Wan Lam, Tak Mak. Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-18.