Table Of ContentDrug Discovery in
Cancer Epigenetics
Translational Epigenetics Series
Trygve O. Tollefsbol, Series Editor
TransgenerationalEpigenetics
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 bySteven G.Gray, 2015
DNA Methylation andComplex Human Disease
By Michel Neidhart,2015
Epigenomics inHealth and Disease
Editedby Mario F. Fraga and Agustin F. Ferna´ndez, 2016
DNA Biomarkers and Diagnostics
Edited by Jose´ Luis Garc´ıa-Gime´nez, 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(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON
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List of Contributors
Paola Arimondo
Unite´ deService etde Recherche, CRDPF,Toulouse, France
Dina Arvanitis
INSERM, UMR1048, Institute ofCardiovascularand Metabolic Diseases, University-Paul
Sabatier, Toulouse,France
Fre´deric Ausseil
Unite´ deService etde Recherche, CRDPF,Toulouse, France
Mina Bekheet
Laboratory ofCancerBiology,Department ofOncology, University ofOxford,Oxford,UK
ChristopherG. Bell
Department ofTwin Research & Genetic Epidemiology,St Thomas’Hospital, King’sCollege
London,London,UK; MRC Lifecourse Epidemiology Unit, University ofSouthampton,
Southampton, UK; Academic Unit ofHuman Development and Health,University of
Southampton, Southampton, UK; EpigenomicMedicine, Centrefor Biological Sciences, Faculty
ofEnvironmentaland Natural Sciences, University ofSouthampton, Southampton, UK
Magdalena Benetkiewicz
GroupeCoope´rateur Multidisciplinaire en Oncologie, Paris, France
Kate H.Brettingham-Moore
SchoolofMedicine, University ofTasmania,Hobart, TAS, Australia
Peter J. Brown
StructuralGenomics Consortium, University of Toronto,Toronto, ON, Canada
Corey Carter
John P.Murtha Cancer Center, WalterReed NationalMilitary Medical Center/National Cancer
Institute,Bethesda, MD, USA
Christophe Cisarovsky
Research Laboratory inOncology,University ofLausanne, Centre Hospitalier Universitaire
Vaudois,Lausanne, Switzerland
Pierre Cordelier
INSERM, UMR1037, Cancer ResearchCenter ofToulouse,University ofToulouse-Paul
Sabatier, Toulouse,France
Armandde Gramont
New Drug Evaluation Laboratory,Centre ofExperimental TherapeuticsandMedical Oncology,
Department ofOncology,University ofLausanne, Centre HospitalierUniversitaire Vaudois,
Lausanne,Switzerland
xv
xvi List of Contributors
Frank J. Dekker
Pharmaceutical Gene Modulation, Groningen ResearchInstitute ofPharmacy, University of
Groningen, Groningen,The Netherlands
Yannick Delpu
Skirball Instituteof Biomolecular Medicine, New York University LangoneMedical Center,
New York, NY,USA
Helmut Dolznig
InstituteofMedical Genetics, Medical University ofVienna, Vienna, Austria
Marle`ne Dufresne
INSERM, UMR1037, Cancer Research Center ofToulouse,University ofToulouse-Paul
Sabatier,Toulouse, France
GerdaEgger
Clinical Institute of Pathology,Medical University ofVienna, Vienna, Austria
ChantalEtievant
Unite´ de Service etde Recherche, CRDPF,Toulouse,France
Sandrine Faivre
Medical Oncology, Department ofOncology,University ofLausanne,CentreHospitalier
Universitaire Vaudois, Lausanne, Switzerland
Gary R.Fanger
EpicentRx, Mountain View,CA, USA
Panagis Filippakopoulos
Structural GenomicsConsortium, Nuffield Department of Clinical Medicine,University of
Oxford,Oxford,UK; LudwigInstitutefor Cancer Research,Nuffield Department ofClinical
Medicine, University ofOxford,Oxford,UK
Alexandre Gagnon
De´partementde Chimie, Universite´ duQue´bec a` Montre´al, Montre´al, QC, Canada
MarionGayral
INSERM, UMR1037, Cancer Research Center ofToulouse,University ofToulouse-Paul
Sabatier,Toulouse, France
MelanieR.Hassler
Clinical Institute of Pathology,Medical University ofVienna, Vienna, Austria
MarkusHengstschla¨ger
InstituteofMedical Genetics, Medical University ofVienna, Vienna, Austria
QuanahJ. Hudson
CeMM Research Center for Molecular Medicine oftheAustrian Academy ofSciences, Vienna,
Austria
List of Contributors xvii
Jean-PierreJ. Issa
Fels Institutefor Cancer Research and Molecular Biology,Temple University School of
Medicine, Philadelphia,PA,USA
Manfred Jung
Institute ofPharmaceutical Sciences, Albert-Ludwigs-Universita¨tFreiburg, Freiburg, Germany
Stefan Knapp
StructuralGenomics Consortium, Nuffield Department ofClinicalMedicine, University of
Oxford,Oxford,UK; Institutefor Pharmaceutical Chemistry,Johann WolfgangGoethe-University,
Frankfurt amMain,Germany
Nina Kramer
Institute ofMedical Genetics, Medical University ofVienna, Vienna,Austria
Stefan Kubicek
CeMM ResearchCenter for MolecularMedicine of theAustrianAcademy ofSciences,
Vienna, Austria; Christian DopplerLaboratory for ChemicalEpigenetics and Antiinfectives,
CeMM ResearchCenter for MolecularMedicine of theAustrianAcademy ofSciences,
Vienna, Austria
Nicholas B.La Thangue
Laboratory ofCancerBiology,Department ofOncology, University ofOxford,Oxford,UK
Dorian Larrieu
INSERM, UMR1037, Cancer ResearchCenter ofToulouse,University ofToulouse-Paul
Sabatier, Toulouse,France
MaximeLeroy
De´partement de Chimie,Universite´ du Que´bec a` Montre´al,Montre´al,QC, Canada
Niek G.J.Leus
Pharmaceutical Gene Modulation, Groningen Research Institute ofPharmacy,University of
Groningen, Groningen,The Netherlands
Marco P. Licciardello
CeMM ResearchCenter for MolecularMedicine of theAustrianAcademy ofSciences,
Vienna, Austria
Marie Lopez
Unite´ deService etde Recherche, CRDPF,Toulouse, France
MichelleLybeck
EpicentRx, MountainView, CA,USA
Wolfgang J. Miller
Laboratoriesof Genome Dynamics, Department ofCell and DevelopmentalBiology,Center of
AnatomyandCellBiology,Medical University of Vienna, Vienna, Austria
xviii List of Contributors
HeidiOlzscha
Laboratory ofCancerBiology,Department of Oncology,University of Oxford, Oxford, UK
Arnold L. Oronsky
InterWestPartners, Menlo Park, CA, USA
Bryan T.Oronsky
EpicentRx, Mountain View,CA, USA
NeilC. Oronsky
CFLS,San Jose, CA, USA
Thomas Prebet
Departement d’Hematologie etUnite d’EvaluationTherapeutique en Oncologie/Hematologie,
InstitutPaoli Calmettes, Marseille, France; Hematology Department,Smilow CancerCenter at
Yale University, New Haven,CT,USA
EricRaymond
Medical Oncology, Department ofOncology,University ofLausanne,CentreHospitalier
Universitaire Vaudois, Lausanne, Switzerland
Noe¨lJ.-M. Raynal
De´partementde Pharmacologie, Universite´ de Montre´al and Sainte-Justine University Hospital
ResearchCenter,Montre´al,QC, Canada
Elisa Redl
Clinical Institute of Pathology,Medical University ofVienna, Vienna, Austria
Tony R.Reid
MooresCancerInstitute, University ofCalifornia, San Diego, CA, USA
Dina Robaa
Institutfu¨rPharmazie, Martin-Luther-Universita¨tHalle-Wittenberg,Halle,Germany
MartinScherzer
InstituteofMedical Genetics, Medical University ofVienna, Vienna, Austria
Jan J. Scicinski
EpicentRx, Mountain View,CA, USA
Semira Sheikh
Laboratory ofCancerBiology,Department of Oncology,University of Oxford, Oxford, UK
Wolfgang Sippl
Institutfu¨rPharmazie, Martin-Luther-Universita¨tHalle-Wittenberg,Halle,Germany
Mira Stadler
InstituteofMedical Genetics, Medical University ofVienna, Vienna, Austria
List of Contributors xix
Phillippa C. Taberlay
Chromatin DynamicGroup,Genomics and Epigenetics Division,Garvan Instituteof Medical
Research, Darlinghurst, NSW,Australia; Epigenetics Program, Genomicsand Epigenetics
Division,Garvan Institute ofMedical Research,Darlinghurst, NSW,Australia; St. Vincent’s
Clinical School, Faculty ofMedicine,University ofNew South Wales,Darlinghurst, NSW,
Australia
Tirza Timmerman,
Pharmaceutical Gene Modulation, Groningen Research Institute ofPharmacy,University of
Groningen, Groningen,The Netherlands
Je´roˆme Torrisani
INSERM, UMR1037, Cancer ResearchCenter ofToulouse,University ofToulouse-Paul
Sabatier, Toulouse,France
Christine Unger
Institute ofMedical Genetics, Medical University ofVienna, Vienna,Austria
Thea van denBosch
Pharmaceutical Gene Modulation, Groningen Research Institute ofPharmacy,University of
Groningen, Groningen,The Netherlands
NorbertVey
Departement d’Hematologie etUnite d’Evaluation Therapeutique en Oncologie/Hematologie,
Institut Paoli Calmettes, Marseille, France;Aix-Marseille Universite´,Marseille, France
TobiasWagner
Institute ofPharmaceutical Sciences, Albert-Ludwigs-Universita¨tFreiburg, Freiburg, Germany
Stefanie Walter
Institute ofMedical Genetics, Medical University ofVienna, Vienna,Austria
Angelika Walzl
Institute ofMedical Genetics, Medical University ofVienna, Vienna,Austria
Daniel J. Weisenberger
USC/Norris Comprehensive Cancer Center,University of Southern California, LosAngeles,
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 validityofthesedrugs 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 diag-
nostic tools, and (v) clinical implications of epigenetic therapy. Emerging concepts, such as “epi-
sensitization,” are also presentedalongside 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 epige-
netic 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
