Drug discovery in cancer epigenetics

Drug Discovery in Cancer Epigenetics Translational Epigenetics Series Trygve O Tollefsbol, Series Editor Transgenerational Epigenetics Edited by Trygve O Tollefsbol, 2014 Personalized Epigenetics Edited by Trygve O Tollefsbol, 2015 Epigenetic Technological Applications Edited by Y George Zheng, 2015 Epigenetic Cancer Therapy Edited by Steven G Gray, 2015 DNA Methylation and Complex Human Disease By Michel Neidhart, 2015 Epigenomics in Health and Disease Edited by Mario F Fraga and Agustin F Fern´andez, 2016 DNA Biomarkers and Diagnostics Edited by Jos´e Luis Garcı´a-Gim´enez, 2016 Drug Discovery in Cancer Epigenetics Edited by Gerda Egger and Paola Arimondo, 2016 Drug Discovery in Cancer Epigenetics Edited by Gerda Egger and Paola Arimondo AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB 225 Wyman Street, Waltham MA 02451 Copyright r 2016 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-802208-5 For information on all Academic Press publications visit our website at http://store.elsevier.com Printed and bound in the United States of America Publisher: Mica Haley Acquisition Editor: Catherine Van Der Laan Editorial Project Manager: Lisa Eppich Production Project Manager: Melissa Read Designer: Mark Rogers List of Contributors Paola Arimondo Unite´ de Service et de Recherche, CRDPF, Toulouse, France Dina Arvanitis INSERM, UMR1048, Institute of Cardiovascular and Metabolic Diseases, University-Paul Sabatier, Toulouse, France ´ Frederic Ausseil Unite´ de Service et de Recherche, CRDPF, Toulouse, France Mina Bekheet Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford, UK Christopher G Bell Department of Twin Research & Genetic Epidemiology, St Thomas’ Hospital, King’s College London, London, UK; MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; Academic Unit of Human Development and Health, University of Southampton, Southampton, UK; Epigenomic Medicine, Centre for Biological Sciences, Faculty of Environmental and Natural Sciences, University of Southampton, Southampton, UK Magdalena Benetkiewicz ´ Groupe Cooperateur Multidisciplinaire en Oncologie, Paris, France Kate H Brettingham-Moore School of Medicine, University of Tasmania, Hobart, TAS, Australia Peter J Brown Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada Corey Carter John P Murtha Cancer Center, Walter Reed National Military Medical Center/National Cancer Institute, Bethesda, MD, USA Christophe Cisarovsky Research Laboratory in Oncology, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Pierre Cordelier INSERM, UMR1037, Cancer Research Center of Toulouse, University of Toulouse-Paul Sabatier, Toulouse, France Armand de Gramont New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland xv xvi List of Contributors Frank J Dekker Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands Yannick Delpu Skirball Institute of Biomolecular Medicine, New York University Langone Medical Center, New York, NY, USA Helmut Dolznig Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Marle`ne Dufresne INSERM, UMR1037, Cancer Research Center of Toulouse, University of Toulouse-Paul Sabatier, Toulouse, France Gerda Egger Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria Chantal Etievant Unite´ de Service et de Recherche, CRDPF, Toulouse, France Sandrine Faivre Medical Oncology, Department of Oncology, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Gary R Fanger EpicentRx, Mountain View, CA, USA Panagis Filippakopoulos Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK Alexandre Gagnon ´ ´ ´ Montreal, ´ QC, Canada Departement de Chimie, Universite´ du Quebec a` Montreal, Marion Gayral INSERM, UMR1037, Cancer Research Center of Toulouse, University of Toulouse-Paul Sabatier, Toulouse, France Melanie R Hassler Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria Markus Hengstschlaăger Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Quanah J Hudson CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria List of Contributors xvii Jean-Pierre J Issa Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA Manfred Jung Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universitaăt Freiburg, Freiburg, Germany Stefan Knapp Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany Nina Kramer Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Stefan Kubicek CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Nicholas B La Thangue Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford, UK Dorian Larrieu INSERM, UMR1037, Cancer Research Center of Toulouse, University of Toulouse-Paul Sabatier, Toulouse, France Maxime Leroy ´ ´ ´ Montreal, ´ QC, Canada Departement de Chimie, Universite´ du Quebec a` Montreal, Niek G.J Leus Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands Marco P Licciardello CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria Marie Lopez Unite´ de Service et de Recherche, CRDPF, Toulouse, France Michelle Lybeck EpicentRx, Mountain View, CA, USA Wolfgang J Miller Laboratories of Genome Dynamics, Department of Cell and Developmental Biology, Center of Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria xviii List of Contributors Heidi Olzscha Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford, UK Arnold L Oronsky InterWest Partners, Menlo Park, CA, USA Bryan T Oronsky EpicentRx, Mountain View, CA, USA Neil C Oronsky CFLS, San Jose, CA, USA Thomas Prebet Departement d’Hematologie et Unite d’Evaluation Therapeutique en Oncologie/Hematologie, Institut Paoli Calmettes, Marseille, France; Hematology Department, Smilow Cancer Center at Yale University, New Haven, CT, USA Eric Raymond Medical Oncology, Department of Oncology, University of Lausanne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Noeăl J.-M Raynal and Sainte-Justine University Hospital Departement de Pharmacologie, Universite´ de Montreal ´ QC, Canada Research Center, Montreal, Elisa Redl Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria Tony R Reid Moores Cancer Institute, University of California, San Diego, CA, USA Dina Robaa Institut fuăr Pharmazie, Martin-Luther-Universitaăt Halle-Wittenberg, Halle, Germany Martin Scherzer Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Jan J Scicinski EpicentRx, Mountain View, CA, USA Semira Sheikh Laboratory of Cancer Biology, Department of Oncology, University of Oxford, Oxford, UK Wolfgang Sippl Institut fuăr Pharmazie, Martin-Luther-Universitaăt Halle-Wittenberg, Halle, Germany Mira Stadler Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria List of Contributors xix Phillippa C Taberlay Chromatin Dynamic Group, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Epigenetics Program, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia Tirza Timmerman, Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands ´ ˆ me Torrisani Jero INSERM, UMR1037, Cancer Research Center of Toulouse, University of Toulouse-Paul Sabatier, Toulouse, France Christine Unger Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Thea van den Bosch Pharmaceutical Gene Modulation, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands Norbert Vey Departement d’Hematologie et Unite d’Evaluation Therapeutique en Oncologie/Hematologie, ´ Marseille, France Institut Paoli Calmettes, Marseille, France; Aix-Marseille Universite, Tobias Wagner Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universitaăt Freiburg, Freiburg, Germany Stefanie Walter Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Angelika Walzl Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria Daniel J Weisenberger USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Preface The causal involvement of epigenetic pathways in tumor development and progression has been widely accepted and recent findings have nourished our knowledge of tumor biology and opened potential clinical applications dependent on epigenetic aberrations Deregulation and mutation of epigenetic enzymes as well as global and local changes of epigenetic chromatin modifications are implicated in a variety of malignancies and provide novel therapeutic and diagnostic targets for oncology There is great interest in developing novel epigenetic drugs targeting chromatin modifiers as well as chromatin reader proteins and some successful recent studies have confirmed the validity of these drugs for cancer therapy We were fortunate to gather many experts and renowned authors to contribute to this book and are very thankful for their efforts and valuable contributions This book intends to provide (i) an introduction into cancer epigenetics and to give a comprehensive overview on, (ii) methods and tools for epigenetic drug development, (iii) classes of epigenetic drugs, (iv) development of diagnostic tools, and (v) clinical implications of epigenetic therapy Emerging concepts, such as “episensitization,” are also presented alongside with indications beyond cancer The intended audience includes both basic scientists as well as clinicians The book is directed toward scientists of the academic and industrial sector, who are aiming to test and develop epigenetic cancer drugs Importantly, the book will increase the awareness level of epigenetic drugs for oncologists We envision that this might foster increased and more rapid translation of epigenetic drugs into the clinics Gerda Egger and Paola Arimondo xxi Index CSC See Cancer stem cells (CSC) CTCF See CCCTC-binding factor (CTCF) CTCL See Cutaneous T-cell lymphoma (CTCL) CTD2 See Cancer Target Discovery and Development (CTD2) CTEP See Cancer Therapy Evaluation Program (CTEP) Cutaneous T-cell lymphoma (CTCL), 195, 335, 381 Cyclic tetrapeptides, 418 Cyclin-dependent kinase (CDK), 386 Cytidine deaminase (CDA), 176 Cytosine, 172f array analysis, 201 D D-2-hydroxyglutarate (2-HG), 155 D4Z4 macrosatellite repeat, 443 DAC See Decitabine (DAC) Dacogen See 5-Aza-20 -deoxycytidine (5-Aza-CdR) DacogenTM See 5-azadeoxycytidine (5azadC) DATECAN program See Definition for Assessment of Timeto-event Endpoints in CANcer trials program (DATECAN program) DCK See Deoxycytidine kinase (DCK) dCMP See Deoxycytidine-50 -monophosphate (dCMP) De novo methylation, 14, 381 De novo methyltransferase, 175 De novo mutation, 443 De novo resistance, 410À411 Deacetylation in NF-κB mediated signaling, 198À199 3-Deazaneplanocin A (DZNep), 148À149, 221, 226, 357 3-Deazauridine (3-DU), 177 Decitabine (DAC), 67, 148, 172f, 332À333, 336À337, 364, 382, 408À409 molecular mechanisms, 173f molecular pharmacology, 172À174 during cell replication, 174 DNA demethylation, 175 montherapy, 331t DEEP See Deutsches Epigenom Programm (DEEP) Definition for Assessment of Time-to-event Endpoints in CANcer trials program (DATECAN program), 130 DELFIA See Dissociation Enhanced Lanthanide FluoroImmuno Assay (DELFIA) Demethylating agents in hematological malignancies, 330, 334 AZA, 330À332, 331t decitabine, 332À333 in solid tumors, 336À337 Demethylating drugs, 439À440 20 -deoxy-5-azacytidylyl-(30 -50 )-20 -deoxyguanosine sodium salt (SGI-110) See Guadecitabine Deoxycytidine kinase (DCK), 172À174 Deoxycytidine-50 -monophosphate (dCMP), 172À174 461 Deregulated epigenetic mechanisms, 23 Dermal equivalent model, 105 Deutsches Epigenom Programm (DEEP), 153 DGF See Digital genomic footprinting (DGF) Diabetes mellitus type (T1DM), 28 Diagnostic marker, 315 Dicer expression, 53 7-Diethylamino-3-(49-maleimidyl-phenyl)-4-methylcoumarin, 72À73 Differential methylation hybridization (DMH), 134 Differential scanning fluorimetry assay (DSF assay), 71À72 Diffuse large B-cell lymphoma (DLBCL), 395 Digital genomic footprinting (DGF), 151 Dinucleotide CpGs See Guanines Direct detection of modified substrates, 216À217 Dissociation Enhanced Lanthanide FluoroImmuno Assay (DELFIA), 71, 217 DLBCL See Diffuse large B-cell lymphoma (DLBCL) DMH See Differential methylation hybridization (DMH) DNA 5-hydroxymethylation, 146 DNA demethylation, 8, 13À14 DNA hypermethylation, 378 DNA methylation, 7À8, 42À43, 83, 123À124, 146, 348À349, 437À438 abnormal hyper-and hypomethylation, 43 and cancer, 375À379 epimutations, 43 patterns, 43À44 strategies for biomarkers, 133À135 subpopulation of tumor cells, 44 targeting, 348À349 DNA methyltransferases (DNMTs), 7, 42À43, 52À53, 64, 82, 146, 170À171, 211À214, 348À349, 375, 409 DNMT1, 312 DNaseI hypersensitivity sequencing (DNaseI-Seq), 46 DNMT inhibitors (DNMTi), 349, 381, 418, 419t approaches to response prediction, 383À384 biomarkers of clinical outcome with DNMT inhibitor therapy, 181À182 clinical trials in hematological malignancies leading, 178 clinical failures, 180 high-risk MDS, 178À179 phase III studies in MDS, 180 single-agent decitabine, 179À180 clinical trials with, 181t lack of efficacy in solid tumors, 182À183 mechanisms, 382 molecular mechanisms of resistance to, 176À178 pharmacological profiling, 83 demethylating effect, 84 special considerations, 84À85 pharmacology azacitidine molecular pharmacology, 175À176 462 Index DNMT inhibitors (DNMTi) (Continued) chemistry of azanucleoside analogs, 171À172 decitabine molecular pharmacology, 172À175 distribution and metabolism, 176 second generation, 183À184 trial evidence, 382À383 DNMTs See DNA methyltransferases (DNMTs) Docking, LO on, 76, 77f Dosage compensation in mammals, 17À18 X chromosome, 18À19 XCI, 18À19 DOT1L, 226À227 Double-strand breaks (DSB), 284 Double-stranded RNAs (dsRNAs), 318À319 Drosha activity, 53 Drosophila D melanogaster, 390 position effect variegation in, 19À20 Drug discovery methods See also Lead optimization (LO) drugÀtarget engagement, 86À87 epigenetics, 64 hit discovery, 65À73 pharmacological profiling, 83 DNMT inhibitors, 83À85 HMT inhibitors, 85À86 Drug repurposing, 68À69 Drug resistance, 176, 178, 414 Drug response in complex models, 110À111 Drug sensitivity, 412À413 DSB See Double-strand breaks (DSB) DSF assay See Differential scanning fluorimetry assay (DSF assay) dsRNAs See Double-stranded RNAs (dsRNAs) 3-DU See 3-deazauridine (3-DU) DZNep See 3-deazaneplanocin A (DZNep) E E2 promoter binding factor (E2F), 378 E2F See E2 promoter binding factor (E2F) EBV See EpsteinÀBarr Virus (EBV) ECM See Extracellular matrix (ECM) Ecogenetic feedback, 410 EDACC See Epigenomics Data Analysis and Coordination Centers (EDACC) EGCG See Epigallocatechin gallate (EGCG) EGFR See Epidermal growth factor receptor (EGFR) EHMT1 lysine methyltransferase, 443 EHMT2 See G9A inhibitors EIF See Entertainment Industry Foundation (EIF) ELISA See Enzyme-linked immunosorbent assay (ELISA) EMA See European Medicines Agency (EMA) Embryonic stem cells (ESC), 7, 151 EMT See Epithelial to mesenchymal transition (EMT) ENCODE See Encyclopedia of DNA Elements (ENCODE) Encyclopedia of DNA Elements (ENCODE), 144, 149À150 Enhancer of zeste homolog (EZH2), 52, 72, 378 Entertainment Industry Foundation (EIF), 161 Entinostat, phase I/II trial with, 427 Enzymatic reaction mechanisms link histone methylation, 211À214 Enzyme panels, hit compounds profiling, 218 Enzyme-linked immunosorbent assay (ELISA), 126À127, 217 Enzymes, 274 See also specific enzymes Epi-resensitization, 409À410 trials, 423 advanced HCC, 424 metastatic colorectal cancer, 424À426 ovarian cancer, 423À424 Epidermal growth factor receptor (EGFR), 410À411 Epidrugs, 329À330 Epigallocatechin gallate (EGCG), 69 Epigenetic drugs, 329À330, 363 discovery ENCODE, 149À150 HEP, 149 ICGC, 157À158 IHEC, 152À154 NREI, 150À152 SGC, 158À160 SU2C epigenetics dream team, 161 TARGET, 156À157 TCGA, 154À156 in hematological malignancies demethylating agents, 330À334 HDACi in, 334À335 inhibitors for cancer therapy, 148À149 Epigenetic mechanisms, 4À6, 347À348, 441 See also Cancer epigenetics chromatin-remodeling complexes and histone variants, 11 DNA demethylation, methylation, 7À8 dosage compensation in mammals, 17À19 epigenetics and disease, 23À28 eukaryotic cells DNA, genomic imprinting as epigenetic silencing model, 15À17 histone acetylation, 8À10 deacetylation, 8À10 demethylation, 10 methylation, 10 modification and nucleosome occupancy, 9f modifications, 8À11 noncoding RNAS, 11À12 PEV in Drosophila, 19À20 phosphorylation, 10 Index and processes, 5f transgenerational and intergenerational epigenetic inheritance, 20À23 Epigenetic reader proteins PHD finger family, 289À290 chemical fragment ligand of Pygo-PHD domain, 292f Halo-Tag-based method, 290 small-molecule ligands of JARID1A-PHD3 domain, 291f Royal family, 276 chromodomain, 282À284 MBT repeat domain, 276À282 PWWP domain, 288À289 Tudor domain, 284À288 Epigenetic readers, targeting, 351 Epigenetic targets for therapeutics, 439 autoimmune and inflammatory disease, 443À445 bromodomains, 440 epigenome, 447 epigenomic modification, 439À440 higher-order chromatin structure remodeling, 439 metabolic and cardiovascular disease, 445À447 neurological diseases, 441À443 potential for epigenetic drugs, 440f US-FDA approved drugs, 440 Epigenetic therapy, 175, 180, 348, 380À381 active in hematological malignancies, 339À340 BRDs and inhibitors, 390À392 DNMT inhibitors, 381À384 epigenetic agents in trials, 381t FDA-approved drugs, 380t HDI, 384À389 solid tumors demethylating agents in, 336À337 HDACi, 337À338, 338t next-generation epigenetic drugs, 338 single-agent hypomethylating agents studies, 337t Epigenetic(s), 4, 64, 123À124, 144, 211, 347À348, 374, 409, 437 aberrant epigenetic modifications, 376f alteration, 312 asymmetry in zygote, 12À14 and cancer, 375À380 changes, 408 chromatin control, 374À375 chromatin structure, 146À148 classes and inhibitors, 416 consecutive immunization strategy, 418 DNMT inhibitors, 418 HDAC inhibitors, 418 multiepigenetic inhibitors, 418À421 oncolytic viruses, 421À422 463 and disease, 23 selected autoimmune diseases, 27À28 selected monogenetic diseases, 23À26, 24t selected neurodegenerative diseases, 26À27 DNA 5-hydroxymethylation, 146 DNA methylation, 146 enzyme mutation, 51 chromatin-remodeling enzymes, 51 DNMT, 52À53 histone modifiers, 52 ncRNA machinery, 53 epigenetic inheritance, transgenerational and intergenerational, 20À23 erasers, 348, 375 genetic and epigenetic characterization efforts in multi-institutional consortia, 145t landscape, 413À414 modifications, 374À375, 438 modifiers, 377t modulation, 411 nucleosome positioning, 146À148 readers, 348, 375 drug combinations, 359À360 regulation of transcription, 352 (re)programming, 12, 13f epigenetic asymmetry in zygote, 12À14 in germline, 14 induced pluripotency, 14À15 silencing model, genomic imprinting as, 15 classical epigenetic process, 15À17 lncRNAs, 17 regulation of imprinted expression, 16f tissue-specific imprinted expression, 17 targeted epigenetic therapies and biomarkers, 375 writers, 348, 375 Epigenetics Dream Team, 161 Epigenetics modifications and Subclinical Atherosclerosis in Obstructive Sleep Apnea study (EPIOSA study), 446 Epigenome, 447 Epigenome-wide association studies (EWAS), 438 in Alzheimer disease, 442 Epigenomic Platform Program, 153 Epigenomics Data Analysis and Coordination Centers (EDACC), 150À151 Episensitization, 408À409 butterfly effect, 411 cancer ecosystem, 410À411 cholangiocarcinoma, 427 epigenetic modulation, 411 NSCLC, 427 Epithelial to mesenchymal transition (EMT), 44 EpsteinÀBarr Virus (EBV), 155 ER See Estrogen receptor (ER) 464 Index Erasers enzymes, 64 Erbituxs See Cetuximab ESC See Embryonic stem cells (ESC) ESCC See Esophageal squamous cell carcinoma (ESCC) Esophageal squamous cell carcinoma (ESCC), 313 Estrogen receptor (ER), 52 Euchromatin, 374 European Medical Agency See European Medicines Agency (EMA) European Medicines Agency (EMA), 171, 333 EWAS See Epigenome-wide association studies (EWAS) Extracellular matrix (ECM), 99 heterotypic 3D coculture models in, 104À106 EZ7438 inhibitor, 335À336 EZH2 inhibitors, 226, 350À351 EZH2 See Enhancer of zeste homolog (EZH2) F 20 -F See 20 -Fluoro (20 -F) F-SPE techniques See Fluorous solid-phase extraction techniques (F-SPE techniques) Facial-scapular-humoral dystrophy (FSHD), 443 FAD See Flavin adenine dinucleotide (FAD) FAIRE-Seq See Formaldehyde-assisted interrogation of regulatory elements sequencing (FAIRE-Seq) FALZ See Fetal Alzheimer Antigen (FALZ) FBDD See Fragment-based drug discovery (FBDD) 5-fC See 5-Formylcytosine (5-fC) FDA See Food and Drug Administration (FDA) Fedratinib, 252À253 Fetal Alzheimer Antigen (FALZ), 246 FFPE See Formaldehyde-fixed, paraffin-embedded (FFPE) Firefly (Fluc), 110À111 Fit-for-purpose method validation, 130À131 FITC See Fluorescein isothiocyanate (FITC) FlashPlates, 72 Flavin adenine dinucleotide (FAD), 68À69 Flavopiridol, 362 Fluc See Firefly (Fluc) Fluor de Lys protocol, 71 Fluorescein isothiocyanate (FITC), 284 Fluorescence polarization (FP), 293À294 Fluorescence recovery after photobleaching (FRAP) assay, 281 5-Fluoro uracil (5-FU), 104 20 -Fluoro (20 -F), 317À318 Fluorous solid-phase extraction techniques (F-SPE techniques), 80 FMR1-AS See Fragile X Mental Retardation antisense (FMR1-AS) FOLFOX4, 415 FOLFOX7, 415 Food and Drug Administration (FDA), 64, 171, 380À381 approved drugs, 440 Formaldehyde-assisted interrogation of regulatory elements sequencing (FAIRE-Seq), 46 Formaldehyde-fixed, paraffin-embedded (FFPE), 105, 110 5-Formylcytosine (5-fC), 146, 437À438 FP See Fluorescence polarization (FP) Fragile X Mental Retardation antisense (FMR1-AS), 313 Fragile X syndrome, 23À24 Fragment-based drug discovery (FBDD), 66À67 FSHD See Facial-scapular-humoral dystrophy (FSHD) FTO gene, 446 5-FU See 5-Fluoro uracil (5-FU) G G9A inhibitors, 69À71 G9a-like protein (GLP), 76 Gametic differentially methylated regions (gDMRs), 15À17 Gastric cancer (GC), 314 Gaussia (Gluc), 110À111 GBM See Glioblastoma multiforme (GBM) GBM patients, temozolomide treatment for, 156 GC See Gastric cancer (GC) GCB lymphoma See Germinal center B-cell-like lymphoma (GCB lymphoma) GCN5 See General control nonderepressible (GCN5) gDMRs See Gametic differentially methylated regions (gDMRs) GDP dissociation inhibitor A (RhoGDI A), 312 General control nonderepressible (GCN5), 193À194 Genistein, 364 Genome-Wide Association Study (GWAS), 442 Genome-wide mechanisms, 439À440 Genomic imprinting as epigenetic silencing model, 15 classical epigenetic process, 15À17 lncRNAs, 17 regulation of imprinted expression, 16f tissue-specific imprinted expression, 17 GenotypeÀphenotype relationship, 446 Germinal center B-cell-like lymphoma (GCB lymphoma), 395 Germline, reprogramming in, 14 GlaxoSmithKline (GSK), 75À76, 158 Glioblastoma multiforme (GBM), 155 GLP See G9a-like protein (GLP) Gluc See Gaussia (Gluc) Goldilocks’ approach, 413 Group isosteres, LO by, 82 GSK See GlaxoSmithKline (GSK) GSK-J4, 359 GSTP1, 393À394 Guadecitabine, 183À184 Guanines, 375À376 GWAS See Genome-Wide Association Study (GWAS) Index H H2AK15ub See Ubiquitinylation mark on histone H2A at lysine 15 (H2AK15ub) H3K27 See Trimethylation of lysine 27 on histone H3 (H3K27) H3K27ac See Acetylation of H3K27 (H3K27ac) H3K27me3 See Histone lysine 27 trimethyl (H3K27me3) H3K4me3 See Histone lysine trimethyl (H3K4me3) H3R2me2a See Asymmetric dimethylation of H3R2 (H3R2me2a) H3R2me2s See Symmetric dimethylation of H3R2 (H3R2me2s) H4R3 See Histone at arginine (H4R3) HATi See Inhibitors of HATs (HATi) HATs See Histone acetyltransferases (HATs) HCC See Hepatocellular carcinoma (HCC) HCC model See Hepatocellular cancer model (HCC model) HCV See Hepatitis C virus (HCV) HDACÀNF-κB interactions in NF-κB signaling, 199À200 HDACs See Histone deacetylases (HDACs) HDI See Histone deacetylase inhibitors (HDACi) HDI-induced antitumor effects, 386 angiogenesis inhibition, 387 apoptotic pathways activation, 386À387 preclinical or clinical trials, 389t selective alteration of gene expression, 386 HDM See Histone demethylases (HDM) HDMi epigenetic combinations, 358À359 Helicobacter pylori (H pylori), 44 HELP See HpaII tiny fragments enrichment by ligationmediated PCR (HELP) Hematological malignancies epigenetic drugs in, 330À336 next-generation epigenetic drugs in, 335À336 Hematopoietic stem and progenitor cells (HSPCs), 109À110 HEP See Human Epigenome Project (HEP) Hepatitis C virus (HCV), 318 Hepatocellular cancer model (HCC model), 105 Hepatocellular carcinoma (HCC), 312, 421 Hepatocyte growth factor (HGF), 109 Heterochromatin, 374 Heterochromatin protein (HP1), 10, 284 Heterogeneity, 412À413 Heterotypic 3D coculture models in ECMs, 104À106 Heterotypic in vitro cancer models, 101f Hexamethylenebisacetamide (HMBA), 67 2-HG See D-2-hydroxyglutarate (2-HG) HGF See Hepatocyte growth factor (HGF) HIF-1α See Hypoxia-inducible factor-1α (HIF-1α) High-throughput screening (HTS), 66, 69, 104, 215, 357 AlphaLISA/AlphaScreen, 69À71 cell-based assays, 71 465 DNA methylation, 71À72 flashplate-based screening, 72 Fluor de Lys protocol, 71 HAT inhibition, 72À73 hits against epigenetic targets, 70t immunoassays, 71 radioactive assays, 72 Histone lysine 27 trimethyl (H3K27me3), 44À45, 409 Histone lysine trimethyl (H3K4me3), 44À45, 146À147, 438, 443 Histone at arginine (H4R3), 66 Histone acetyltransferases (HATs), 8À9, 52, 64, 146À149, 192, 240, 350, 375, 418, 439 classes, 193À194 Histone deacetylase inhibitors (HDACi), 87, 192, 316, 329À330, 348, 384, 416, 418, 420t, 439, 444 as anti-inflammatory drugs for treatment of inflammation, 200À202 in cancer, 195À196 classification, 384À386 and clinical outcomes, 387À388 HDI-induced antitumor effects, 386 angiogenesis inhibition, 387 apoptotic pathways activation, 386À387 preclinical or clinical trials, 389t selective alteration of gene expression, 386 in hematological malignancies, 334À335 main classes of, 385f mechanisms of action, 197À198 single-agent clinical trials in AML/MDS, 334t in solid tumors, 337À338, 338t Histone deacetylases (HDACs), 7À8, 52, 64, 192, 240, 350, 375, 409, 439 classes, 194À195, 240 HDAC1, 148 inhibition activities, 195t Histone demethylases (HDM), 64, 350, 375 Histone lysine methylation chromatin modifiers, 213f global and locus-specific control, 210 proteinÀprotein interactions, 214À215 Histone methylation, 10, 350À351 assaying, 215 biochemical assays, 215À218 cell-based assays, 218À219 enzymatic reaction mechanisms linking, 211À214 hottest therapeutic targets in, 225 DOT1L, 226À227 EZH2 inhibitors, 226 LSD1 inhibitors, 227 methylation drugs of future, 227À228 regulation, 210À211 Histone methylation, targeting, 219 See also Histone methylation 466 Index Histone methylation, targeting (Continued) irreversible inhibitors of LSD1/2, 222À224 JMJC demethylases metabolic targeting of, 224 small-molecule inhibitors binding active sites, 224À225 LSD1 inhibitors, 224 methylation modulators of future, 225 methyltransferases, 219À221 allosteric and indirect inhibition, 222 SAM-binding pocket, 222 targeting peptide-binding pocket, 221À222 PADS, 225 PRMTS, 225 Histone methyltransferases (HMTs), 64, 146À147, 274, 350, 391 and demethylases binding assays for, 215À216 chemical probes for, 223f crystal structures, 220f inhibitors pharmacological profiling, 85 special considerations, 86 in wild-type cells, 85À86 Histone-methylating enzymes, 214À215 Histone(s), 6, 197 acetylation, 8À10, 350À351 and cancer, 379À380 code, 44À45, 239À240, 352, 374 deacetylation, 8À10 demethylation, 10 histone-modifying enzymes, 148 modifications, 8À11, 44À45, 123À124, 192, 350 modifiers, 52 phosphorylation, 10 protein octamers, 438 readers, 274À275, 295 tail, 374À375 Hit compounds profiling, 218 Hit discovery, 65, 65f drug repurposing, 68À69 exploring natural products, 69 FBDD, 66À67 HTS, 69À73, 70t hybrid inhibitor design, 68 in silico screening and molecular docking, 65À66 structure-based approaches, 67À68 “Hit-to-lead” See Lead optimization (LO) HIV-1 See Human immunodeficiency virus-1 (HIV-1) HMBA See Hexamethylenebisacetamide (HMBA) 5hmC See 5-hydroxymethylcytosine (5hmC) hMLH1 silencing, 360À361 HMTi epigenetic combinations, 357 DZNep, 357 high-throughput screenings, 357 MLL, 357À358 HMTs See Histone methyltransferases (HMTs) Homogeneous tests, 72 Homogeneous time-resolved fluorescence (HTRF), 217 HOTAIR See HOX transcript antisense intergenic RNA (HOTAIR) HOX transcript antisense intergenic RNA (HOTAIR), 50, 310, 313À315 HP1 See Heterochromatin protein (HP1) HpaII tiny fragments enrichment by ligation-mediated PCR (HELP), 134 HPV See Human papilloma virus (HPV) HR23B See Human ultraviolet excision repair protein RAD23 homolog B (HR23B) HSPCs See Hematopoietic stem and progenitor cells (HSPCs) HTRF See Homogeneous time-resolved fluorescence (HTRF) HTS See High-throughput screening (HTS) HTT-AS expression See Huntington antisense expression (HTT-AS expression) Human cancers, CIMP subgroups, 155 Human Epigenome Project (HEP), 144, 149 Human genome project, 123À124 Human immunodeficiency virus-1 (HIV-1), 289 Human papilloma virus (HPV), 44 Human ultraviolet excision repair protein RAD23 homolog B (HR23B), 388 Huntington antisense expression (HTT-AS expression), 313 Huntington disease, 26À27, 442 Hybrid inhibitor design, 68 Hydroxamic acids, 355À356, 418 5-Hydroxymethylation See 5-Hydroxymethylcytosine (5hmC) 5-Hydroxymethylcytosine (5hmC), 8, 146, 437À438 Hypomethylating agents, 416 Hypomethylation, 375À376 Hypoxia-inducible factor-1α (HIF-1α), 387 I IAP See Intracisternal A particle (IAP) ICEs See Imprint control elements (ICEs) ICGC See International Cancer Genomics Consortium (ICGC) ICM assay See In vivo Complex of Methylase assay (ICM assay) IDH See Isocitrate DeHydrogenase (IDH) IFNγ See Interferon γ (IFNγ) IHC See Immunohistochemistry (IHC) IHEC See International Human Epigenome Consortium (IHEC) IL-1 See Interleukin-1 (IL-1) IL6 See Interleukin (IL6) Imitation-SWI (ISWI), 246 “Immediate-early” genes, 10 Immune cells, 109À110 Immunohistochemistry (IHC), 105 Index IMP See Research Institute of Molecular Pathology (IMP) Imprint control elements (ICEs), 15À17 In silico screening and molecular docking, 65À66 In vitro models for tumor cells intravasation/extravasation, 106 In vivo Complex of Methylase assay (ICM assay), 86 In vivo human cancer models, 102f In vivo models, 107 PDX models, 108À109 standard xenograft models, 107 xenograft models in humanized mice, 109À110 xenograft models with human stroma, 109 Inactive X (Xi), Indirect detection methods, 217À218 Induced pluripotency, 14À15 Induced pluripotent stem cells (iPS cells), 15, 151 inducible nitric oxide synthase (iNOS), 199 Inhibitors of 2-oxoglutarate-dependent hydroxylases, 224À225 Inhibitors of HATs (HATi), 192 in cancer, 194 iNOS See inducible nitric oxide synthase (iNOS) Interferon γ (IFNγ), 201 Intergenerational epigenetic inheritance, 20 agouti gene locus, 21 chemical substances, 21À22 chromatin-based mechanisms, 22À23 in plants, 22 Interleukin (IL6), 109 Interleukin-1 (IL-1), 198 Intermittent dosing, 415À416 International Cancer Genomics Consortium (ICGC), 144, 157À158 International Human Epigenome Consortium (IHEC), 144, 152À154 Intracisternal A particle (IAP), 13À14, 21 iPS cells See Induced pluripotent stem cells (iPS cells) IRX3 transcription factor gene, 446 Isocitrate DeHydrogenase (IDH), 64 IDH1, 214 IDH2, 214, 375À376 Isothermal calorimetry (ITC), 277 ISWI See Imitation-SWI (ISWI) ITC See Isothermal calorimetry (ITC) IκBs, 198 J JMJC demethylases metabolic targeting of, 224 small-molecule inhibitors binding active sites, 224À225 JQ1, 351, 359À360 Jumonji C (JmjC), 210À211 Jumonji C domain-containing HDMs (JHDMs), 79 Jumonji C-containing demethylases, 358À359 467 K K120 See Acetylation of lysine 120 (K120) K120R mutant, 379 “K4me3-R8me2a” pattern, 285À288 KAc See Acetylated lysine residues (KAc) Kasumi-1 (KG1), 84 KAT domain See Lysine acetyltransferase domain (KAT domain) KDM See Lysine demethylase (KDM) KG1 See Kasumi-1 (KG1) Kinase-inducible domain (KIX), 241À243 KMTs See Lysine methyltransferases (KMTs) L L3MBTL1-MBT domain small-molecule “biophysical” probes for, 279f small-molecule ligands, 278f, 280f L3MBTL1, 276À277, 280f L3MBTL3, 278À279, 282 unique binding mode, 281f Lanthanide chelate excite technology (LANCE technology), 69 LBH589, 362À363 Lead optimization (LO), 67, 73, 81f in absence of structural information, 73 on docking, 76, 77f by SAR data, 73À76 lead generation, 79 lead identification from literature compounds, 82 LO by group isosteres, 82 LO by transposition of key pharmacophores, 80À82 LO using parallel or combinatorial chemistry tools, 80 via target hopping approaches, 82À83 via SAR studies, 74f using structural information, 76, 78f using mechanism-or ligand-based approach, 79 using structure-based design approach, 76À79 LEC See Lymph endothelial cells (LEC) Lens epithelium-derived growth factor (LEDGF), 289 Leukotriene B4 receptor locus, 445 Ligand-based approach, LO using, 79 lincRNAs See Long intergenic ncRNAs (lincRNAs) LINE-1 See Long interspersed element (LINE-1) Lipopolysaccharide (LPS), 198 Lit-to-lead approach, 82 LNA See Locked nucleic acid (LNA) LncRNAs See Long noncoding RNAs (LncRNAs) LO See Lead optimization (LO) Locked nucleic acid (LNA), 318 anti-miRs, 318 468 Index Long intergenic ncRNAs (lincRNAs), 310, 313À314 Long interspersed element (LINE-1), 383À384 methylation, 334 Long noncoding RNAs (LncRNAs), 4, 15À17, 47À50, 144, 148, 309, 315, 439 See also Small non-coding RNAs circRNAs, 314 lincRNAs, 310, 313À314 NATs, 309À310, 313 non-coding pseudogenes, 310À311 T-UCRs, 310, 313 LSD See Lysine-specific demethylase (LSD) LSD1 inhibitors, 224, 227 Lymph endothelial cells (LEC), 106 Lysine acetylation, 192, 239À240, 274 regulation of NF-κB activity by, 200f Lysine acetyltransferase domain (KAT domain), 80 Lysine demethylase (KDM), 67À68 Lysine methyltransferases (KMTs), 274 Lysine-specific demethylase (LSD), 358 LSD1, 67À68, 310 M Major histocompatibility complex (MHC), 149 MALAT-1 See Metastasis-associated lung adenocarcinoma transcript (MALAT-1) MALDI-TOF-MS See Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) Malignant brain tumor (MBT), 275 Malignant brain tumor domain (MBT domain), 351 Marker Validation of Erlotinib in Lung Cancer (MARVEL), 132À133 Mass-spectrometry (MS), 87, 126À127 Maternally expressed gene (MEG3), 316 Matrix metallopeptidase (MMP-9), 316 Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), 135 Maximum tolerated dose (MTD), 169À170 MBDs See Methyl-CpG binding domain proteins (MBDs) MBT See Malignant brain tumor (MBT) MBT domain See Malignant brain tumor domain (MBT domain) MBT repeat domain, 276À277 FRAP assay, 281 L3MBTL1-MBT domain small-molecule “biophysical” probes for, 279f small-molecule ligands, 278f, 280f L3MBTL1, 277, 280f L3MBTL3, 278À279, 282 unique binding mode, 281f para-bromophenyl sulfonamides, 277 traditional pulldown assays, 281 5mC See 5-Methylcytosine (5mC) MCA See Methylated CpG island amplification (MCA) MCP-1 See Monocyte chemoattractant protein-1 (MCP-1) mCRC See Metastatic colorectal cancer (mCRC) MCTS See Multicellular tumor spheroids (MCTS) MDB See Methyl-binding proteins (MDB) MDS See Myelodysplastic syndrome (MDS) 5MeC See 5-Methylcytosine (5mC) MeCP2 See Methyl-CpG binding protein (MeCP2) MeDIP See Methylated DNA immunoprecipitation (MeDIP) MeDIP-seq See Methylated DNA immunoprecipitation sequencing (MeDIP-seq) MEG3 See Maternally expressed gene (MEG3) Mendelian inheritance, 20 Mental retardation syndrome, 25 [2S,4S]-4-Mercaptopyrrolidine-2-carboxylic acid, 67 messenger RNAs (mRNAs), 307À308 Meta/meta isomer, 82 Metabolic and cardiovascular disease, 445À446 See also Autoimmune and inflammatory disease; Neurological diseases atherosclerosis, 446 changes in DNA methylation, 446 EPIOSA study, 446 FTO gene, 446 genotypeÀphenotype relationship, 446 monogenic disease, 447 Metastasis-associated lung adenocarcinoma transcript (MALAT-1), 313À314 Metastatic colorectal cancer (mCRC), 414, 424 clinical trial schema, 425f decline of CEA levels, 426f phase I study of SGI-110 combined with irinotecan, 426 randomized phase II clinical trial of RRx-001 vs regorafenib, 424À426 Metastatic renal cell carcinoma (MRCC), 316 Methyl-binding proteins (MDB), 64 Methyl-CpG binding domain proteins (MBDs), 146 Methyl-CpG binding protein (MeCP2), 289, 437À438 Methyl-lysine readers, 275À276 See also Epigenetic reader proteins computational methods, 294À295 Methylated CpG island amplification (MCA), 134 Methylated CpG island recovery assay (MIRA), 134 Methylated DNA immunoprecipitation (MeDIP), 134 Methylated DNA immunoprecipitation sequencing (MeDIPseq), 151 Methylated restriction enzyme sequencing (MRE-seq), 151 Methylation-sensitive cut counting (MSCC), 134 5-Methylcytosine (5mC), 8, 12À13, 146, 375À376 O-6-Methylguanine methyltransferase (MGMT), 156, 360 DNA methylation, 156 2-4(4-Methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT), 69À71, 228 Methylstat, 224À225 Index Methyltransferases, 219À221 allosteric and indirect inhibition, 222 SAM-binding pocket, 222 targeting peptide-binding pocket, 221À222 20 -O-methyoxyethyl (20 -MOE), 317À318 Metronomic dosing, 415 MGCD0103, 196 MGMT See O-6-Methylguanine methyltransferase (MGMT) MHC See Major histocompatibility complex (MHC) Microarray-based methylation assessment of single samples (MMASS), 134 Micrococcal nuclease sequencing (MNase-Seq), 46 Microfluidic systems, 104 microRNAs (miRNAs), 11, 47À48, 144, 147À148, 307À308, 312 DNA methylation signatures, 49 expression profiles, 315 expression signature, 48 miR-200 levels, 49 oncogenic, 48 sponge vector, 319 tumor-suppressive, 48À49 Microsatellite instability (MSI), 43, 155 Microsource Spectrum, 71À72 MiR-21 expression, 312 MIRA See Methylated CpG island recovery assay (MIRA) “miRNA seed” sequences, 307À308 miRNAs See microRNAs (miRNAs) Mismatch repair (MMR), 43 Mixed lineage leukemia (MLL), 252, 292À293, 350À351 MLH1 See MutL homolog (MLH1) MLL See Mixed lineage leukemia (MLL); Myeloid/lymphoid leukemia (MLL) MM See Multiple myeloma (MM) MMASS See Microarray-based methylation assessment of single samples (MMASS) MMP-9 See Matrix metallopeptidase (MMP-9) MMR See Mismatch repair (MMR) MNase-Seq See Micrococcal nuclease sequencing (MNase-Seq) MoA See Mode of action (MoA) Mocetinostat See MGCD0103 Mode of action (MoA), 73 20 -MOE See 20 -O-methyoxyethyl (20 -MOE) Molecular signature, 392 Monoallelic expression, 15 Monocyte chemoattractant protein-1 (MCP-1), 100À101 Monocytic zinc finger protein (MOZ finger protein), 69À71, 379 Monogenic disease, 447 Monoubiquitylation of histone H2A (uH2A), 26À27 MOZ finger protein See Monocytic zinc finger protein (MOZ finger protein) 469 MRCC See Metastatic renal cell carcinoma (MRCC) MRE-seq See Methylated restriction enzyme sequencing (MRE-seq) mRNAs See messenger RNAs (mRNAs) MS See Mass-spectrometry (MS); Multiple sclerosis (MS) MS-based cellular assays, 219 MSCC See Methylation-sensitive cut counting (MSCC) MSI See Microsatellite instability (MSI) MTD See Maximum tolerated dose (MTD) MTD-associated “cell kill” paradigm, 415 Multicellular tumor spheroids (MCTS), 100 Multiepigenetic inhibitors, 418À421 Multiple myeloma (MM), 312, 381 Multiple sclerosis (MS), 23, 28 Multistep screening process, 71À72 MutL homolog (MLH1), 43 Myelodysplastic syndrome (MDS), 6, 43À44, 68, 148, 171, 329À330, 349 Myeloid/lymphoid leukemia (MLL), 357À358 MLL1 gene, 443 MYOD1 promoter hypermethylation, 393À394 N NATs See Natural antisense transcripts (NATs) Natural antisense transcripts (NATs), 309À310, 313 Natural products, 69 NCI See US National Cancer Institute (NCI) ncRNAs See Noncoding RNAs (ncRNAs) NDR See Nucleosome-depleted region (NDR) Neoplastic cells, 348À349 Neurological diseases, 441 See also Autoimmune and inflammatory disease; Metabolic and cardiovascular disease autism, 443 epigenetic mechanisms, 441 epigenetic priming and lineage commitment of neuronal progenitors, 443 EWAS in Alzheimer disease, 442 FSHD, 443 Huntington’s disease, 442 immune role in multiple sclerosis, 442 Parkinson disease, 442 piRNAs, 441 UBE3A gene, 441À442 valproic acid, 442 New molecular entities (NMEs), 97À98 Next-generation epigenetic drugs in hematological malignancies, 335À336 in solid tumors, 338 Next-generation sequencing techniques (NGS techniques), 134 NF-κB See Nuclear factor κB (NF-κB) 470 Index NF-κB-mediated inflammation, HDACi as anti-inflammatory drugs for treatment of, 200À202 NGS techniques See Next-generation sequencing techniques (NGS techniques) NHGRI See United States National Human Genome Research Institute (NHGRI) NHL See Non-Hodgkin lymphoma (NHL) NIH See United States National Institutes of Health (NIH) NIH Roadmap Epigenomics Initiative (NREI), 144, 150À151 DNA methylation, 151 ENCODE, 152 REMCs, 151À152 series of reports, 152 NMC See NUT midline carcinoma (NMC) NMD See Nonsense-mediated decay (NMD) NMEs See New molecular entities (NMEs) NMR See Nuclear magnetic resonance (NMR) NOMe-Seq See Nucleosome occupancy and methylation sequencing (NOMe-Seq) Non-coding pseudogenes, 310À311 Non-Hodgkin lymphoma (NHL), 73À75, 337À338 Noncoding RNAs (ncRNAs), 11À12, 42f, 47À48, 306 altered ncRNA expression, 311 classes, 306, 311 classification and function, 307f LncRNAs, 49À50, 309 circRNAs, 314 lincRNAs, 310, 313À314 NATs, 309À310, 313 non-coding pseudogenes, 310À311 T-UCRs, 310, 313 miRNAs, 48À49 piRNAs, 50À51 small ncRNAs miRNAs, 307À308, 312 piRNA, 308, 312 snoRNAs, 308, 312À313 snRNAs, 308À309, 313 targeting strategies for treatment of human diseases, 316, 317f ASOs, 316À318 exogenous siRNAs, 318À319 miRNA sponge vector, 319 small molecules, 319À320 utility of ncRNA biomarkers for human diseases, 314 diagnostic marker, 315 predictive markers of therapeutic response, 315À316 prognostic marker, 315 Nonepigenetic resensitization strategies, 416, 417f Nonsense-mediated decay (NMD), 309 Nonsmall-cell lung cancer (NSCLC), 148, 315, 414, 427 Nontoxic agent combination, 364 Noresensitization rule, 414 NREI See NIH Roadmap Epigenomics Initiative (NREI) NSCLC See Nonsmall-cell lung cancer (NSCLC) NSD1/2/3 enzymes, 228 Nuclear factor κB (NF-κB), 192, 378 mediated signaling acetylation and deacetylation in, 198À199 HDACÀNF-κB interactions in, 199À200 regulation of NF-κB activity by lysine acetylation, 200f Nuclear magnetic resonance (NMR), 290À291 Nuclear protein in testis (NUT), 351 Nucleoporin protein 98 (NUP98), 290 Nucleoside analogs, 169À170 Nucleosome occupancy and methylation sequencing (NOMeSeq), 46 Nucleosome remodeling and deacetylase (NuRD), 51 Nucleosome-depleted region (NDR), 147 Nucleosomes, 374À375 depletion, 46À47 with histone tail, 275f occupancy, 151 positioning, 146À148 positions and higher-order structures, 46À47 Null hypothesis, 423 NUP98 See Nucleoporin protein 98 (NUP98) NuRD See Nucleosome remodeling and deacetylase (NuRD) NUT See Nuclear protein in testis (NUT) NUT midline carcinoma (NMC), 251À252, 391 O OCG See US Office of Cancer Genomics (OCG) Octamer-binding transcription factor (OCT4), 314 Olfactory imprinting, 22 Oncolytic viruses (OVs), 421 ONYX-015, 422 viral vectors, 422 virotherapy trials, 422 Oncometabolite, 214 Oncostatic viruses, 422 ONYX-015, 422 Open chromatin structure, 239À240 Open reading frame (ORF), 309 OPTIMOX-1 trial, 415À416 Optoepigenetics approach, 447 ORF See Open reading frame (ORF) “Organoid” models, 103À104 Organotypic spheroid model, 105À106 ORRs See Overall response rates (ORRs) OS See Overall survival (OS) OTX015 BET bromodomain inhibitor, 363 OVs See Oncolytic viruses (OVs) Ovarian cancer, 423 phase I/II study of 5-azacytidine and carboplatin, 423À424 phase II clinical trial of DAC and carboplatin, 423 Index Overall response rates (ORRs), 382À383 Overall survival (OS), 330À331, 409 Oxaliplatin-related neuropathy, 415 P p21 inhibitor, 386 p300/CBP associated factor (PCAF), 193À194 p53 DNA-binding domain, 379 p53-binding protein (53BP1), 284 PAD enzymes See Peptidylarginine deiminase enzymes (PAD enzymes) Pan assay interference compounds (PAINS), 69 “Pan-Cancer” analyses, 154À155 Pan-HDACi, 201, 444 Panitumumab, 414 Panobinostat, 388 PAR regions See Pseudoautosomal regions (PAR regions) Parallel chemistry tools, LO using, 80 Parkinson disease, 26, 442 Partial response (PR), 423À424 PASRs See Promoter-associated small RNAs (PASRs) “Passive” resensitization events, 414 Patient-derived tumor xenograft models (PDX models), 108À109 PBAF See Polybromo and Brg1-associated factor (PBAF) PBIT See 2-4(4-Methylphenyl)-1,2-benzisothiazol-3(2H)one (PBIT) PBMCs See Peripheral blood mononuclear cells (PBMCs) PC4 and SFRS1 interacting protein (PSIP1), 289 PCAF See p300/CBP associated factor (PCAF) PD See Pharmacodynamics (PD) PDB See Protein Data Bank (PDB); Protein database (PDB) PDP1 See PWWP domain protein (PDP1) PDX models See Patient-derived tumor xenograft models (PDX models) Peptidylarginine deiminase enzymes (PAD enzymes), 225, 444À445 Peripheral blood mononuclear cells (PBMCs), 100À101, 200À201, 444 Peripheral T-cell lymphoma (PTCL), 195, 381 PEV See Position effect variegation (PEV) PFS See Progression-free survival (PFS) PGCs See Primordial germ cells (PGCs) PGR See Progesterone receptor (PGR) Pharmacodynamics (PD), 104, 125 biomarkers, 393 Pharmacokinetics (PK), 73, 104 Pharmacologic mechanism, 176À177 Pharmacological profiling, 83 DNMT inhibitors, 83 demethylating effect, 84 special considerations, 84À85 HMT inhibitors, 85 471 special considerations, 86 in wild-type cells, 85À86 PHD See Plant homeodomain (PHD) Phenylbutyrate, 355À356 Phosphatase and tensin homolog (PTEN), 48 Phosphorylation, 10 Pilot three-arm study of RRx-001, 427 PIWI-interacting RNAs (piRNAs), 50À51, 308, 312, 441 PK See Pharmacokinetics (PK) Plant homeodomain (PHD), 241À243, 275 domains, 351 epigenetic reader proteins chemical fragment ligand of Pygo-PHD domain, 292f Halo-Tag-based method, 290 small-molecule ligands of JARID1A-PHD3 domain, 291f fingers, 289À290 Platinum-refractory disease, 423 ovarian cancer, 416 Platinum-resistant disease, 423 Platinum-responsive disease, 423 PML See Promyelocytic leukemia (PML) Polybromo and Brg1-associated factor (PBAF), 245 Polycomb repressive complexes (PRC), 45, 282 PRC1, 309 PRC2, 12, 50, 72, 147, 310, 378 Position effect variegation (PEV), in Drosophila, 19À20 Post-translational modifications (PTMs), 239À240, 274 POU domain class transcription factor 1B (POU5F1B), 314 PPP See PublicÀprivate partnership (PPP) PR See Partial response (PR) PraderÀWilli syndrome (PWS), 25, 312À313 PRC See Polycomb repressive complexes (PRC) Preclinical cancer models cell culture in 2D, 98À99 drug response in complex models, 110À111 epigenetic mechanisms, 99 homotypic 3D in vitro cancer models, 98f NMEs, 97À98 remodeling human cancers, 99À110 subcutaneous models, 99 Preclinical in vitro models cancer on chip models, 104 cancer organoid models, 103À104 cell encapsulation models, 103 heterotypic 3D coculture models in ECMs, 104À106 heterotypic in vitro cancer models, 101f spheroid models, 100À102 in vitro models for tumor cells intravasation/extravasation, 106 in vivo human cancer models, 102f 472 Index Predictive biomarkers, 126À128 biomarker-based therapies, 128À129 BRAF mutations, 128 Predictive markers of therapeutic response, 315À316 pri-miRNAs See Primary miRNAs (pri-miRNAs) Primary miRNAs (pri-miRNAs), 307À308 Prime-boost See Consecutive immunization strategy Priming, 409 Primordial germ cells (PGCs), 12 PRMTs See Protein arginine methyltransferases (PRMTs) Pro-Trp-Trp-Pro (PWWP) domain, 288À289 Procaine, 68 Progesterone receptor (PGR), 393À394 Prognostic biomarkers, 392 Prognostic marker, 315 Progression-free survival (PFS), 423 Promoter upstream transcripts (PROMPTs), 311 Promoter-associated small RNAs (PASRs), 311 PROMPTs See Promoter upstream transcripts (PROMPTs) Promyelocytic leukemia (PML), 246, 379À380 Protein arginine methyltransferases (PRMTs), 225 PRMT2, 285À288 PRMT4, 82 Protein Data Bank (PDB), 158 Protein database (PDB), 295 ProteinÀprotein interactions, 214À215 Proteins, 274 Pseudoautosomal regions (PAR regions), 18À19 Pseudogenes, 310À311, 314 PSIP1 See PC4 and SFRS1 interacting protein (PSIP1) PTCL See Peripheral T-cell lymphoma (PTCL) PTEN See Phosphatase and tensin homolog (PTEN) PTEN pseudogene (PTENpg1), 50 PTMs See Post-translational modifications (PTMs) PublicÀprivate partnership (PPP), 158 PWS See PraderÀWilli syndrome (PWS) PWWP See Pro-Trp-Trp-Pro (PWWP) PWWP domain protein (PDP1), 288 Pygo PHD finger, 290À291 Q Quasi-quantitative assay real-time quantitative reverse transcription PCR-based assay (qRT-PCR-based assay), 131 R RA See Rheumatoid arthritis (RA) Radioactive assays, 72 Radioactive-based methods, 217 Raft culture model, 105 Rapamycin, 363 RARS See Arginyl-tRNA synthetase (RARS) Rb See Retinoblastoma (Rb) “Reader” proteins, 8, 64, 274 RECIST See Response Evaluation Criteria in Solid Tumors (RECIST) Recombinant wild-type assay, 73À75 Reduced representation bisulfite sequencing (RRBS), 134À135, 151 Reference Epigenome Mapping Centers (REMC), 150À151 Remodeling human cancers, 99À100 explant cultures, 106À107 preclinical in vitro models cancer on chip models, 104 cancer organoid models, 103À104 cell encapsulation models, 103 heterotypic 3D coculture models in ECMs, 104À106 heterotypic in vitro cancer models, 101f spheroid models, 100À102 in vitro models for tumor cells intravasation/ extravasation, 106 in vivo human cancer models, 102f in vivo models, 107 PDX models, 108À109 standard xenograft models, 107 xenograft models in humanized mice, 109À110 xenograft models with human stroma, 109 Reporter-based cellular assays, 219 Research Institute of Molecular Pathology (IMP), 71 Resensitization, 409 Resistance, 411À412 See also Episensitization adaptive therapy, 413 epigenetic classes and specific inhibitors, 416À422 epigenetic landscape, 413À414 heterogeneity, 412À413 hypomethylating agents, 416 intermittent dosing, 415À416 metronomic dosing, 415 sensitization/resensitization strategies, 413 treatment holidays, 413À414 Resminostat, 424 Response Evaluation Criteria in Solid Tumors (RECIST), 124 Response rate (RR), 414 Restriction landmark genome scanning (RLGS), 134 Retinoblastoma (Rb), 378 Retinoic acids, 356 Retrospective-prospective approach, 132 RetrospectiveÀprospective study design, 132 Rett syndrome (RS), 25, 443 RG108, 66 RGD acid See ArginineÀglycineÀaspartic acid (RGD acid) Rheumatoid arthritis (RA), 27À28 RhoGDI A See GDP dissociation inhibitor A (RhoGDI A) Ribosomal RNAs (rRNAs), 309 RISC See RNA-induced silencing complex (RISC) RLGS See Restriction landmark genome scanning (RLGS) RNA interference techniques, 442 Index RNA-induced silencing complex (RISC), 307À308 ROCKET study, 421 Romidepsin, 387À388 RR See Response rate (RR) rRNAs See Ribosomal RNAs (rRNAs) RRx-001, 418À421 RS See Rett syndrome (RS) RubinsteinÀTaybi syndrome (RTS), 24À25 S S-adenosyl-homocysteine (SAH), 67, 211À214 turnover, 219À221 S-adenosylmethionine (SAM), 66, 146, 211À214 Saccharomyces cerevisiae (S cerevisiae), 384 SAH See S-adenosyl-homocysteine (SAH) SAM See S-adenosylmethionine (SAM) Sanger-based sequencing methods, 143À144 SAR studies See StructureÀactivity relationship studies (SAR studies) Scintillation Proximity Assay (SPA), 72 SCLC See Small-cell lung cancers (SCLC) SD See Stable disease (SD) SDH See Succinate dehydrogenase (SDH) Secondary resistance See De novo resistance Selected autoimmune diseases, 27À28 Selected monogenetic diseases, 23À24, 24t BeckwithÀWiedemann syndrome, 25À26 mental retardation syndrome, 25 PraderÀWilli and Angelman syndromes, 25 Rett syndrome (RS), 25 RubinsteinÀTaybi syndrome (RTS), 24À25 Selected neurodegenerative diseases, 26À27 SFRP2, 358 SGC See Structural Genomics Consortium (SGC) SGI-110, 334 Single nucleotide polymorphism (SNP), 154, 279 Single-agent hypomethylating agents studies, 337t Single-molecule real-time sequencing (SMRT), 134À135 siRNAs See Small interfering RNAs (siRNAs) Sirtuins (SIRT), 194À195, 384 SLE See Systemic lupus erythematosus (SLE) Small interfering RNAs (siRNAs), 318À319 Small molecule inhibitors, 194 HATi in cancer, 194 HATs classes, 193À194 HDACi in cancer, 195À196 HDACs classes, 194À195 inhibition activities on Class I HDACs, 195t NF-κB mediated signaling acetylation and deacetylation in, 198À199 HDACÀNF-κB interactions in, 199À200 regulation of NF-κB activity by lysine acetylation, 200f WDR5ÀMML interaction, 294f 473 Small molecules, 216, 319À320 BRDs inhibition by, 252À253 Small non-coding RNAs See also Long noncoding RNAs (LncRNAs) miRNAs, 307À308, 312 piRNA, 308, 312 snoRNAs, 308, 312À313 snRNAs, 308À309, 313 Small nuclear RNAs (snRNAs), 308À309, 313 Small nucleolar ribonucleoproteins (snoRNPs), 308 Small nucleolar RNAs (snoRNAs), 50À51, 308, 312À313 Small RNA sequencing (smRNA-seq), 151 Small-cell lung cancers (SCLC), 227 SMARCA4 expression, 251 SMCHD1 chromatin regulator, 443 smRNA-seq See Small RNA sequencing (smRNA-seq) SMRT See Single-molecule real-time sequencing (SMRT) SNCA See α-synuclein (SNCA) snoRNAs See Small nucleolar RNAs (snoRNAs) snoRNPs See Small nucleolar ribonucleoproteins (snoRNPs) SNP See Single nucleotide polymorphism (SNP) snRNAs See Small nuclear RNAs (snRNAs) Solid tumors DNMT inhibitors lack of efficacy, 182À183 epigenetic therapies demethylating agents, 336À337 HDACi, 337À338, 338t next-generation epigenetic drugs, 338 single-agent hypomethylating agents studies, 337t Sorafenib, 424 SPA See Scintillation Proximity Assay (SPA) SPECS See Strategic Partnering to Evaluate Cancer Signatures (SPECS) Spheroid models, 100À102 Spindlin1, 285À288 Stable disease (SD), 423À424 Stand Up to Cancer (SU2C), 144 Stand Up to Cancer Epigenetics Dream Team (SU2C Epigenetics Dream Team), 161 Standard chemotherapy, 360À362 Standard xenograft models, 107 STELLA, 13À14 Strategic Partnering to Evaluate Cancer Signatures (SPECS), 156 Structural Genomics Consortium (SGC), 76, 144, 158 consortium members, 158À159 JQ1, 159À160 PPP and public domain, 160f structural information, 159À160 Swedish Granting Agencies, 159 Structure-based approaches, 67À68 StructureÀactivity relationship studies (SAR studies), 73, 278, 290À291 lead optimization by, 73, 74f Constellation Pharmaceuticals, 75 474 Index StructureÀactivity relationship studies (SAR studies) (Continued) recombinant wild-type assay, 73À75 structural information, 76 SU2C See Stand Up to Cancer (SU2C) SU2C Epigenetics Dream Team See Stand Up to Cancer Epigenetics Dream Team (SU2C Epigenetics Dream Team) Suberoylanilide hydroxamic acid (SAHA) See Vorinostat Succinate dehydrogenase (SDH), 214 Suppressor of zeste (SUZ2), 319 Surrogate endpoint, 392 Surrogates, LO by, 82 SUZ2 See Suppressor of zeste (SUZ2) SWI/SNF See Switch/sucrose nonfermentable (SWI/SNF) Switch/sucrose nonfermentable (SWI/SNF), 86 Symmetric dimethylation of H3R2 (H3R2me2s), 292 Systematic resensitization, 416 Systemic lupus erythematosus (SLE), 23, 27 T T-UCR See Transcribed ultraconserved regions (T-UCR) T1D See Type diabetes (T1D) T1DM See Diabetes mellitus type (T1DM) T2D See Type diabetes (T2D) TAFII250, 245 TALENs See Transcription activator-like effector nucleases (TALENs) TAR RNA-binding protein (TRBP), 319À320 TARGET See Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Target engagement, monitoring, 126À127 Target hopping approaches, lead generation via, 82À83 Targeted chemotherapy kinase inhibitor, 362À363 Targeted epigenetic therapies, 375 TAT interacting protein 60 (Tip60), 193À194, 379 TATA box binding protein (TBP), 245 TBP See TATA box binding protein (TBP) TCF See Transcription factors (TF) TCGA See The Cancer Genome Atlas (TCGA) Temozolomide treatment for GBM patients, 156 TenÀeleven translocation (TET), 64, 375À376 TET See TenÀeleven translocation (TET) Tet methylcytosine dioxygenase (TET1), 146 Tet methylcytosine dioxygenase (TET2), 383À384 TET1 See Tet methylcytosine dioxygenase (TET1) TET2 See Tet methylcytosine dioxygenase (TET2) TF See Transcription factors (TF) TG-101348 See Fedratinib The Cancer Genome Atlas (TCGA), 144, 154 CIMP subgroups of human cancers, 155 MGMT DNA methylation, 156 “Pan-Cancer” analyses, 154À155 Therapeutically Applicable Research to Generate Effective Treatments (TARGET), 144, 156À157 Thermal shift, 215À216 ThermoFAD, 215À216 Thermofluor, 215À216 Time-resolved fluorescence resonance energy transfer (TRFRET), 69 Tip60 See TAT interacting protein 60 (Tip60) tiRNAs See Transcription initiation RNAs (tiRNAs) TKIs See Tyrosine kinase inhibitors (TKIs) TNF See Tumor necrosis factor (TNF) TR-FRET See Time-resolved fluorescence resonance energy transfer (TR-FRET) TRAIL See Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Transcribed ultraconserved regions (T-UCR), 50, 310, 313 Transcription, 240À241 Transcription activator-like effector nucleases (TALENs), 447 Transcription factors (TF), 290À291, 378 Transcription initiation RNAs (tiRNAs), 311 Transcription start site (TSS), 147 Transcription start site-associated RNAs (TSS-RNAs), 311 Transgenerational epigenetic inheritance, 20 agouti gene locus, 21 chemical substances, 21À22 chromatin-based mechanisms, 22À23 in plants, 22 Tranylcypromine, 358À359 TRBP See TAR RNA-binding protein (TRBP) Treatment holidays, 413À414 Trichostatin A (TSA), 67À68, 199, 355À356, 387 TRIM See Tripartite motif (TRIM) Trimethylation of lysine 27 on histone H3 (H3K27), 72, 378 Tripartite motif (TRIM), 241 Triple epigenetic inhibitor, 421 TSA See Trichostatin A (TSA) TSGs See Tumor-suppressor genes (TSGs) TSS See Transcription start site (TSS) TSs See Tumor slices (TSs) TSS-RNAs See Transcription start site-associated RNAs (TSS-RNAs) Tudor domain, 284 fragment-like ligand, 285f implementation in cancer development and progression, 286t Polycomb PRC2 complex, 285 Spindlin1, 285À288 Tudor-domain-containing protein, 288 UNC2170, 285 Tumor cells intravasation/extravasation, in vitro models for, 106 Tumor necrosis factor (TNF), 386 TNF-α, 198 Index Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 382 Tumor progression, 42À43 Tumor slices (TSs), 106À107 Tumor-on-chip models, 104 Tumor-suppressor genes (TSGs), 42À43 Type diabetes (T1D), 445 Type diabetes (T2D), 445À446 Tyrosine 641 (Y641), 85 Tyrosine kinase inhibitors (TKIs), 414 U UBE3A See Ubiquitin E3 ligase gene (UBE3A) UBE3A antisense transcript (UBE3A-AS), 316À317 Ube3a-ATS, 441À442 Ubiquitin E3 ligase gene (UBE3A), 25, 316À317, 441À442 Ubiquitinylation mark on histone H2A at lysine 15 (H2AK15ub), 284 UCRs See Ultraconserved regions (UCRs) uH2A See Monoubiquitylation of histone H2A (uH2A) Ultraconserved regions (UCRs), 310 UNC See University of North Carolina (UNC) UNC13B gene, 445 United States National Human Genome Research Institute (NHGRI), 150 United States National Institutes of Health (NIH), 150À151 University of North Carolina (UNC), 76 30 -untranslated region (30 -UTR), 307À308 US National Cancer Institute (NCI), 156 US Office of Cancer Genomics (OCG), 156 30 -UTR See 30 -untranslated region (30 -UTR) UVI5008, 421 V Valproic acid (VPA), 68, 386À387, 442 Vargula luciferase (Vluc), 110À111 Vascular endothelial growth factor (VEGF), 316, 387 Vectibixs See Panitumumab VEGF See Vascular endothelial growth factor (VEGF) Vidaza See Azacitidine (AZA) Viral vectors, 422 Vluc See Vargula luciferase (Vluc) Vorinostat, 67, 148, 335, 387 VPA See Valproic acid (VPA) 475 W Waddington’s epigenetic landscape, 414f Warburg effect, 410 WD40 repeat domain family, 292 arginine residue, 293À294 small-molecule inhibitors of WDR5ÀMML interaction, 294f WDR5 recognition of arginine residues, 293f WDR5, 292À293 WD40 repeat protein (WDR5), 292À293 WDR5ÀMLL1 interaction, 292À293 WGBS See Whole-genome bisulfite sequencing (WGBS) WGSGS See Whole genome shotgun bisulfite sequencing (WGSGS) “White-mottled” eye, 19 Whole genome shotgun bisulfite sequencing (WGSGS), 134À135 Whole-genome bisulfite sequencing (WGBS), 151 Whole-genome sequencing, 147, 374 WHSC1 See WolfÀHirschhorn syndrome candidate (WHSC1) Win motif, 292À293 WolfÀHirschhorn syndrome candidate (WHSC1), 289 Writers enzymes, 64 Writers proteins, 274 X X chromosome inactivation (XCI), Xenograft models with human stroma, 109 in humanized mice, 109À110 standard, 107 Xi See inactive X (Xi) Xist expression, 18 Y Y641 See Tyrosine 641 (Y641) yeast HDAC (yHda1), 384À385 Z Zebularine, 172f Zinc Finger E-Box Binding Homeobox gene (ZEB2 gene), 310 Zygote, epigenetic asymmetry in, 12À14 ... domains are currently known to bind methylated DNA: the SET and RING finger-associated domain, found in UHRF1 and UHRF2 and zinc fingers, found in Kaiso and Kaiso-like proteins [49] Methyl-CpG-binding... Differentiation Lineage commitment Noncoding RNA Disease Loss of imprinting Mutation in genes regulating epigenetics Loss/gain of epigenetic marks Deamination of MeC Genomic instability FIGURE... Edited by Jos´e Luis Garcı´a-Gim´enez, 2016 Drug Discovery in Cancer Epigenetics Edited by Gerda Egger and Paola Arimondo, 2016 Drug Discovery in Cancer Epigenetics Edited by Gerda Egger and Paola