(Methods in Molecular Biology 1175) Qing Yan (eds.)-Pharmacogenomics in Drug Discovery and Developme

Unformatted text preview: Methods in Molecular Biology 1175 Qing Yan Editor Pharmacogenomics in Drug Discovery and Development Second Edition METHODS IN M O L E C U L A R B I O LO G Y Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hatfield, Hertfordshire, AL10 9AB, UK For further volumes: Pharmacogenomics in Drug Discovery and Development Second Edition Edited by Qing Yan PharmTao, Santa Clara, CA, USA Editor Qing Yan PharmTao Santa Clara, CA, USA ISSN 1064-3745 ISSN 1940-6029 (electronic) ISBN 978-1-4939-0955-1 ISBN 978-1-4939-0956-8 (eBook) DOI 10.1007/978-1-4939-0956-8 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2014939325 © Springer Science+Business Media New York 2014 This work is subject to copyright. 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It is a rapidly growing area in the recognition of the necessity of personalized medicine, a medicine that deals with the complexity of the human body. Because of the diversity of patients’ biological backgrounds, the same disease may be caused by genetic variations in different people, who will respond differently to the same drug. Such situations require individualized treatment that avoids adverse drug responses and ensures the best possible results. The development of pharmacogenomics represents the evolution of biomedicine from treating the disease itself to treating the malfunction of an individual person, the “root” of diseases. With the change of focus from disease-centered to human-centric medicine, pharmacogenomics brings hope for the transformation from simple disease treatment to accurate prediction and effective prevention. For the drug discovery and development industry, pharmacogenomics is useful in identifying drug targets to obtain the optimal drug efficacy for specific patient groups. However, many challenges need to be resolved before pharmacogenomics can be applied in the clinic. Most importantly, the mechanisms inside the human bodies that control therapeutic responses are complex and multifactorial. It is necessary to elucidate the complexity in various spatial and temporal levels, such as the interactions among genes, drugs, as well as natural and psychosocial environments at various physiological and pathological stages. Accurate biomarkers and effective drug targets can be found only based on such understanding at system levels. In this book, we approach these challenges from several angles. In the first part of the book, we introduce some novel concepts and important cutting-edge technologies that are useful for the development of system-based pharmacogenomics to solve the complexity (see Part I). A framework of systems and dynamical medicine is proposed on the basis of the understanding of the properties of complex adaptive systems (CASs) (see Chapter 1). Various “omics” technologies such as approaches in bioinformatics and transcriptomics are described to support the system analyses (see Chapters 2 and 3). These methods are useful for understanding the complex and dynamical interconnections and interactions among genes, drugs, diseases, and the environment. Network and dynamical models can be established for the identification of robust biomarkers to evaluate disease states, disease progression, and therapeutic responses (see Chapter 1). For example, bioinformatics is essential in finding the spatiotemporal patterns in pharmacogenomics, including the time-series analyses for the elucidation of structure–function associations at various disease stages. Specific experimental methods are also introduced, such as the mutational analysis procedures on paraffin-embedded tumors for the prediction of individual responses to anticancer therapy (see Chapter 4). The combination of bioinformatics and experimental approaches is helpful for studying drug adverse effects such as those caused by statin, including genotyping, phenotyping, and statistical analysis strategies (see Chapter 5). Another feature of this volume is the emphasis on the examinations of gene–drug interactions, that is, how drugs act and how they are processed in the human body, including drug absorption, distribution, metabolism, and excretion. Biomarkers and molecules v vi Preface such as ion channels, membrane transporters, receptors, and enzymes are playing increasingly essential roles in drug design and pharmacogenomics studies (see Chapters 6, 7, 8, and 9). These biomarkers provide critical links between drug discovery and diagnostics efforts. Updated introductions and detailed methods about studies in these molecules are provided in this book. For example, membrane transporters are profoundly involved in drug disposition through transporting substrate drugs between organs and tissues. Investigations of genetic variations, genotyping methods, and substrate identification of membrane transporters are helpful for drug design and development (see Chapter 6). Methods for the clinical development of transporter markers can be meaningful for the practice of translational medicine. In addition, studies of G protein-coupled receptors (GPCRs) may provide insight into disease pathways, such as the involvement of the regulator of G protein signaling (RGS) protein polymorphisms in hypertension. Pharmacogenomics of GPCR studies the involvement of genetic variations in structural and functional roles, such as GPCR activation and inactivation, their relationships with diseases, and their potential uses in defining optimized novel drug targets (see Chapters 7, 8, and 9). These investigations can be useful for refining drug discovery because GPCR disorders are associated with a wide variety of human diseases, including obesity, diabetes, cardiovascular diseases, cancer, asthma, and infectious diseases. The second part of this book focuses on how to translate pharmacogenomics studies from the “bench side” to the “bedside” in clinical therapies of diseases to support the development of translational medicine (see Part II). These diseases include cardiovascular diseases, cancer, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, osteoporosis, and pediatric diseases. Comprehensive information for each disease system is discussed, including biomarkers involved in the diseases and the associations among genes, diseases, drug responses, and the environment. For example, genetic variations may play important roles in heart failure pharmacotherapy (see Chapter 10). Pharmacogenomics studies are making significant contributions toward the elucidation of pharmacological atheroprotection for finding novel therapeutic approaches for atherosclerosis, the condition that can result in stroke, myocardial infarction, and death (see Chapter 11). In cancer therapy, translational investigations in pharmacogenomics may also make genetic profiling effective for the analysis of chemotherapy-induced neurotoxicity (CIPN) (Chapter 12). As a complex disorder with multifactorial clinical features, Alzheimer’s disease (AD) needs to be studied in the context of diverse environmental impacts, cerebrovascular dysfunction, epigenetic phenomena, as well as various structural and functional genomic dysfunctions (see Chapter 13). This book provides a comprehensive and detailed discussion of the pharmacogenomics of AD, from functional genomics to therapeutic strategies, from the discovery of reliable biomarkers to the optimized drug development. The identification of pharmacogenomic biomarkers for the prediction of drug efficacy and adverse reactions is a growing area of research in the studies of psychiatric disorders such as schizophrenia (see Chapter 14). Such methods have the potential to replace the current trial-and-error approach for the optimal treatment selections toward the personalized medicine. Pharmacogenomics investigations may also elucidate the roles of genetic, biological, social, and environmental components in the therapeutic responses of drug addiction (see Chapter 15). For rheumatoid arthritis (RA), the pharmacogenomics of traditional disease-modifying antirheumatic drugs (DMARDs) as well as the newer biologic DMARDs are discussed in details for individualized therapy (see Chapter 16). In addition, with comprehensive examinations including genome-wide association studies, exciting opportunities are open to provide a better insight into the pharmacogenomics of osteoporosis and osteoporotic fractures Preface vii (see Chapter 17). In pediatrics, developmental changes may account for the variability in drug responses. Various “omics” approaches including genome-wide haplotype mapping, proteomics, epigenomics, as well as genetic epidemiological studies over years may expand the scope of personalized therapies in children (see Chapters 18 and 19). By covering topics from individual molecules to systemic diseases, from basic concepts to advanced technologies, this book intends to provide a practical, state-of-the-art, and integrative view of the application of pharmacogenomics in drug discovery and development. A wide range of theoretical and experimental approaches are introduced to meet the problem-solving objectives for understanding the complexity in health and diseases, from laboratory tests to computational analysis. Written by leading experts in the field, this book intends to provide comprehensive resources and a holistic view for the translation of pharmacogenomics into better preventive and personalized medical care. I would like to thank all of the authors for their valuable contributions to this exciting field. I also thank the series editor, Dr. John Walker, for his help with the editing. Santa Clara, CA, USA Qing Yan, M.D., Ph.D. Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PART I SYSTEMS AND “OMICS” STUDIES IN PHARMACOGENOMICS 1 From Pharmacogenomics and Systems Biology to Personalized Care: A Framework of Systems and Dynamical Medicine . . . . . . . . . . . . . . . . . . . . . Qing Yan 2 Translational Bioinformatics Approaches for Systems and Dynamical Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Qing Yan 3 Whole Blood Transcriptomic Analysis to Identify Clinical Biomarkers of Drug Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Grant P. Parnell and David R. Booth 4 Diagnostic Procedures for Paraffin-Embedded Tissues Analysis in Pharmacogenomic Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raffaele Palmirotta, Maria Laura De Marchis, Giorgia Ludovici, Patrizia Ferroni, Pasquale Abete, Fiorella Guadagni, and David Della-Morte 5 Approach to Clinical and Genetic Characterization of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . QiPing Feng 6 Pharmacogenetics of Membrane Transporters: A Review of Current Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tristan M. Sissung, Andrew K.L. Goey, Ariel M. Ley, Jonathan D. Strope, and William D. Figg 7 G Protein-Coupled Receptor Accessory Proteins and Signaling: Pharmacogenomic Insights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miles D. Thompson, David E.C. Cole, Pedro A. Jose, and Peter Chidiac 8 G Protein-Coupled Receptor Mutations and Human Genetic Disease . . . . . . . Miles D. Thompson, Geoffrey N. Hendy, Maire E. Percy, Daniel G. Bichet, and David E.C. Cole 9 Pharmacogenetics of the G Protein-Coupled Receptors. . . . . . . . . . . . . . . . . . Miles D. Thompson, David E.C. Cole, Valerie Capra, Katherine A. Siminovitch, G. Enrico Rovati, W. McIntyre Burnham, and Brinda K. Rana PART II v xi 3 19 35 45 67 91 121 153 189 CLINICAL APPLICATIONS OF PHARMACOGENOMICS 10 Pharmacogenomics of Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anastasios Lymperopoulos and Faren French ix 245 x Contents 11 Pharmacogenomics in the Development and Characterization of Atheroprotective Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Efi Valanti, Alexandros Tsompanidis, and Despina Sanoudou 12 Management of Side Effects in the Personalized Medicine Era: Chemotherapy-Induced Peripheral Neuropathy. . . . . . . . . . . . . . . . . . . . . . . . Paola Alberti and G. Cavaletti 13 Pharmacogenomics of Alzheimer’s Disease: Novel Therapeutic Strategies for Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ramón Cacabelos, Pablo Cacabelos, Clara Torrellas, Iván Tellado, and Juan C. Carril 14 Pharmacogenetics of Antipsychotic Treatment in Schizophrenia . . . . . . . . . . . Jennie G. Pouget and Daniel J. Müller 15 Pharmacogenetics of Addiction Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David A. Nielsen, Ellen M. Nielsen, Teja Dasari, and Catherine J. Spellicy 16 Pharmacogenetics in Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . Deepali Sen, Jisna R. Paul, and Prabha Ranganathan 17 Pharmacogenomics of Osteoporotic Fractures . . . . . . . . . . . . . . . . . . . . . . . . . José A. Riancho and Flor M. Pérez-Campo 18 Pharmacogenomics and Pharmacoepigenomics in Pediatric Medicine . . . . . . . Barkur S. Shastry 19 Pharmacogenomics in Children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael Rieder Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 301 323 557 589 625 661 671 687 709 Contributors PASQUALE ABETE • Department of Clinical Medicine, Cardiovascular Science and Immunology, Cattedra di Geriatria, University of Naples Federico II, Naples, Italy PAOLA ALBERTI • Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy DANIEL G. BICHET • Department of Physiology and Medicine, Hôpital du Sacré-Coeur, Université de Montréal, Montréal, QC, Canada DAVID R. BOOTH • Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia W. MCINTYRE BURNHAM • Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada PABLO CACABELOS • EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, Camilo José Cela University, Madrid, Spain RAMÓN CACABELOS • EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, Camilo José Cela University, Madrid, Spain VALERIE CAPRA • Laboratory of Molecular Pharmacology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy JUAN C. CARRIL • EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, Camilo José Cela University, Madrid, Spain G. CAVALETTI • Department of Surgery and Translational Medicine, University of Milano-Bicocca, Monza, Italy PETER CHIDIAC • Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada DAVID E.C. COLE • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada TEJA DASARI • Biochemistry and Cell Biology, Rice University, Houston, TX, USA DAVID DELLA-MORTE • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy; Department of System Medicine, University of Rome Tor Vergata, Rome, Italy QIPING FENG • Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN, USA PATRIZIA FERRONI • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy WILLIAM D. FIGG • Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA FAREN FRENCH • Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USA ANDREW K.L. GOEY • Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA xi xii Contributors FIORELLA GUADAGNI • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy GEOFFREY N. HENDY • Departments of Medicine, Physiology and Human Genetics, McGill University, Montreal, QC, Canada; Calcium Research Laboratory and, Hormones and Cancer Research Unit, Royal Victoria Hospital and McGill University Health Centre, Montreal, QC, Canada PEDRO A. JOSE • Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA ARIEL M. LEY • Molecular Pharmacology Program, National Cancer Institute, Bethesda, MD, USA GIORGIA LUDOVICI • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy ANASTASIOS LYMPEROPOULOS • Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USA MARIA LAURA DE MARCHIS • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy DANIEL J. MÜLLER • Pharmacogenetics Research Clinic, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada DAVID A. NIELSEN • Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA; Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA ELLEN M. NIELSEN • Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA RAFFAELE PALMIROTTA • Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy GRANT P. PARNELL • Westmead Millennium Institute, University of Sydney, Sydney, NSW, Australia JISNA R. PAUL • Division of Rheu...
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