Textbook of Personalized Medicine

Textbook of Personalized Medicine

Second Edition

Kewal K. Jain, MD, FRACS, FFPM Jain PharmaBiotech, Basel, Switzerland Kewal K. Jain Jain PharmaBiotech Basel , Switzerland

ISBN 978-1-4939-2552-0 ISBN 978-1-4939-2553-7 (eBook) DOI 10.1007/978-1-4939-2553-7

Library of Congress Control Number: 2015934582

Springer New York Heidelberg Dordrecht London © Springer Science+Business Media New York 2014, 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.

Printed on acid-free paper

Humana Press is a brand of Springer Springer Science+Business Media LLC New York is part of Springer Science+Business Media (www.springer.com) “Tonight, I’m launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes — and to give all of us access to the personalized information we need to keep ourselves and our families healthier.” —President Barack Obama, State of the Union Address, 20 January 2015, USA

Preface to the Second Edition

Considerable advances have taken place in technologies used for advancing person- alized medicine, and it is increasingly applied in clinical use. This has required expansion and revision of some parts of the fi rst edition published in 2009. The style has been maintained due to the positive feedback of readers, including scientists, pharmacists, physicians, and lay persons interested in this topic. The book provides a concise and comprehensive source of reference for those involved in healthcare management, planning, and politics. As a single author book, it avoids the overlaps and missing areas frequently found in multiauthor books. Moreover, the time to publication is reduced by avoiding the long delays of numerous authors who do not keep the deadlines. The book includes 700 references selected from thousands of publications during the past decade and appended at the end of each chapter. Some of the references included were prepublication versions at the end of 2014 that will not be formally published until 2015. The text is supplemented by 31 illustrations and 56 tables. Algorithms are included as a guide to those involved in the management of important diseases where decision making is involved due to the multiple choices available. Finally, I thank the editorial staff of Springer, particularly Patrick Marton and David Casey, for their help and encouragement in this project.

Basel, Switzerland Kewal K. Jain

vii

Preface to the First Edition

Personalized medicine, which simply means selection of treatment best suited for an individual, involves integration and translation of several new technologies in clinical care of patients. The scope is much broader than indicated by the term genomic medicine, because many non-genomic factors are taken into consideration in developing personalized medicine. Basic technologies for personalized medicine, of which molecular diagnostics has the biggest share, are mentioned briefl y and appropriate references are given for further information. Commercial aspects are discussed briefl y in a chapter and detailed analysis of markets and companies involved in personalized medicine is presented in a special report on this topic. There is increasing interest in personalized medicine. Considerable advances have taken place in molecular biology and biotechnology to make personalized medicine a viable option, but some misconceptions still exist, both in the academic and in the commercial sectors. There is lack of a suitable source of information that provides both the fundamentals as well as applications of personalized medicine. As the lat- est version of the fi rst monograph on personalized medicine published in 1998, this volume, Textbook of Personalized Medicine , summarizes the author’s efforts during the past decade as well as reviews of selected studies done during this period in a readable format for physicians and scientists. It is hoped that physicians, pharma- cists, scientists, and interested lay readers with basic scientifi c knowledge will fi nd this book useful.

Basel, Switzerland Kewal K. Jain

ix

About the Author

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been work- ing in the biotechnology/biopharmaceuticals industry for several years. He received graduate training in both Europe and USA, has held academic positions in several countries, and is a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of UK. Currently, he is a consultant at Jain PharmaBiotech. He has been working on developing personalized therapy by integrating new tech- nologies in addition to since 1997. His monograph with the title Personalized Medicine published in 1998 was the fi rst treatise on this topic. Over the years, it went through several editions until it evolved into the Textbook of Personalized Medicine, published by Springer in 2009. It was translated into Japanese in 2012 and the current version is the second edition of this book. Professor Jain’s 452 publications include 25 books (5 as editor + 20 as author) and 50 special reports, which have covered important areas in biotechnology, gene therapy, and biopharmaceuticals. His important recent books include Handbook of Nanomedicine (Springer 2008; Chinese edition, Peking University Press 2011; 2nd ed Springer 2012), Handbook of Biomarkers (Springer 2010), Handbook of Neuroprotection (Springer 2010), Drug-induced Neurological Disorders , 3rd ed (Hogrefe 2011), Applications of Biotechnology in Cardiovascular Disorders (Springer 2011), Applications of Biotechnology in Neurology (Springer 2013), and Applications of Biotechnology in Oncology (Springer 2014). He has edited Applied Neurogenomics (January 2015).

xi

Contents

1 Basic Aspects ...... 1 Defi nition of Personalized Medicine ...... 1 History of Medical Concepts Relevant to Personalized Medicine ...... 3 Molecular Biological Basis of Personalized Medicine ...... 6 The Human Genome ...... 6 Chromosomes ...... 7 Genes ...... 8 Genetic Variations in the Human Genome ...... 10 Interconnected Genetic and Genomic Patterns in Human Diseases ..... 17 Basics Technologies for Developing Personalized Medicine ...... 18 Defi nitions of Technologies Relevant to Personalized Medicine ...... 18 Problems with the ICH Defi nitions of and Pharmacogenetics ...... 19 ‘’ and Personalized Medicine ...... 19 Relationship of Various Technologies to Personalized Medicine ...... 20 Conventional Medicine Versus Personalized Medicine ...... 20 Personalized Medicine and Evidence-Based Medicine ...... 21 Role of Genetics in Future Approaches to Healthcare ...... 21 Genetic Medicine ...... 21 Human Disease and Genes ...... 22 Genetic and Environmental Interactions in Etiology of Human Diseases ...... 22 Role of Genetics in Development of Personalized Medicines ...... 23 Role of in Personalized Medicine ...... 26 Systems Pharmacology ...... 27 Systems Medicine ...... 28 Synthetic Biology and Development of Personalized Medicines ...... 29 Integration of Technologies for Personalized Medicine ...... 30 Reclassifi cation of Diseases ...... 31 Translational Science and Personalized Medicine ...... 32 References ...... 32

xiii xiv Contents

2 Molecular Diagnostics in Personalized Medicine ...... 35 Introduction ...... 35 Molecular Diagnostic Technologies ...... 36 PCR-Based Methods ...... 37 Non-PCR Methods ...... 39 DNA Sequencing ...... 40 Role of Sequencing in Personalized Medicine ...... 40 Whole Genome Sequencing and Personalized Medicine ...... 40 RNA Sequencing ...... 42 Whole Exome Sequencing and Personalized Disease Risk ...... 42 Personal ...... 44 Biochips and Microarrays ...... 44 Role of Biochip/Microarray Technology in Personalized Medicine ..... 45 Applications of Biochip/Microarray Technology in Personalized Medicine ...... 45 Biochip Technologies ...... 47 Standardizing the Microarrays ...... 50 Optical Mapping ...... 51 Biosensor Technologies for Biochips ...... 52 Protein Biochips ...... 53 Microfl uidics ...... 56 SNP Genotyping ...... 58 Genotyping and Haplotyping ...... 59 Technologies for SNP Analysis ...... 62 Biochip and Microarray-Based Detection of SNPs ...... 62 Detection of Copy Number Variations ...... 70 Digital Array for CNV Detection ...... 71 CNVer Algorithm for CNV Detection ...... 71 CNVnator for Discovery of CNVs and Genotyping ...... 71 Study of Rare Variants in Pinpointing Disease-Causing Genes ...... 72 Application of in Molecular Diagnosis ...... 73 Proteomic Technologies ...... 73 Comparison of Proteomic and Genomic Approaches in Personalized Medicine ...... 75 Gene Expression Profi ling ...... 76 DNA Microarrays ...... 77 Analysis of Single-Cell Gene Expression ...... 78 Gene Expression Profi ling Based on Alternative RNA Splicing ...... 78 Gene Expression Analysis on Biopsy Samples ...... 79 Profi ling Gene Expression Patterns of White Blood Cells ...... 79 Serial Analysis of Gene Expression ...... 80 Monitoring In Vivo Gene Expression by Molecular Imaging ...... 81 Molecular Imaging and Personalized Medicine ...... 81 Combination of Diagnostics and Therapeutics ...... 82 Use of Molecular Diagnostics for Stratifi cation in Clinical Trials ...... 82 Companion Diagnostics ...... 83 Contents xv

Point-of-Care Diagnosis ...... 84 Advantages Versus Disadvantages of Point-of-Care Diagnosis ...... 85 Future Prospects of Point-of-Care Diagnosis ...... 86 Genetic Testing for Disease Predisposition ...... 86 Preventive Genetics by Early Diagnosis of Mitochondrial Diseases .... 87 Direct-to-Consumer Genetic Services ...... 87 Future of Molecular Diagnostics in Personalized Medicine ...... 87 References ...... 88 3 Role of Biomarkers in Personalized Medicine ...... 91 Introduction ...... 91 Biomarkers and Diagnostics ...... 91 Expression Signatures as Diagnostic/Prognostic Tools ...... 92 Role of Biomarkers in Development of Personalized Drugs ...... 93 Drug Rescue by Biomarker-Based Personalized Medicine ...... 93 Biomarkers for Monitoring Response to Therapy ...... 94 to Sort Biomarker Data for Personalized Medicine ...... 95 Use of Bayesian Approach in Biomarker-Based Clinical Trials ...... 95 Concluding Remarks ...... 96 References ...... 97 4 Pharmacogenetics ...... 99 Basics of Pharmacogenetics ...... 99 Role of Molecular Diagnostics in Pharmacogenetics ...... 100 Role of Pharmacogenetics in Pharmaceutical Industry ...... 101 Study of the Drug Metabolism and Pharmacological Effects ...... 101 Causes of Variations in Drug Metabolism ...... 101 Enzymes Relevant to Drug Metabolism ...... 102 Pharmacogenetics of Phase I Metabolism ...... 103 Pharmacogenetics of Phase II Metabolism ...... 108 Measurement of CYP Isoforms ...... 110 Polymorphism of Drug Transporters ...... 111 Genetic Variation in Drug Targets ...... 111 Effect of Genetic Polymorphisms on Disease Response to Drugs ...... 112 Ethnic Differences in Drug Metabolism ...... 113 Gender Differences in Pharmacogenetics ...... 114 Role of Pharmacogenetics in Drug Safety ...... 115 Therapeutic Drug Monitoring, Phenotyping, and Genotyping ...... 126 Phenomics ...... 128 Molecular Toxicology in Relation to Personalized Medicines ...... 130 Pharmacogenetics in Clinical Trials...... 132 Postmarketing Pharmacogenetics ...... 133 Clinical Implications of Pharmacogenetics ...... 134 Application of CYP450 Genotyping in Clinical Practice ...... 134 Pharmacogenomic Biomarker Information in Drug Labels ...... 134 Genotype-Based Drug Dose Adjustment ...... 134 xvi Contents

Use of Pharmacogenetics in Clinical Pharmacology ...... 141 Application of CYP2C19 Pharmacogenetics for Personalized Medicine ...... 141 Genotyping for Identifying Responders to Sulfasalazine ...... 141 HLA Alleles Associated with Lumiracoxib-Related Liver Injury ...... 141 Pharmacogenetic Basis of Thiopurine Toxicity ...... 142 Tranilast-Induced Hyperbilirubinemia due to Gene Polymorphism ..... 143 Linking Pharmacogenetics with Pharmacovigilance ...... 143 Recommendations for the Clinical Use of Pharmacogenetics ...... 144 Limitations of Pharmacogenetics ...... 144 Pharmacoepigenomics vs Pharmacogenetics in Drug Safety ...... 145 Future Role of Pharmacogenetics in Personalized Medicine ...... 146 References ...... 147 5 Pharmacogenomics ...... 149 Introduction ...... 149 Basics of Pharmacogenomics ...... 149 Pharmacogenomics vs Pharmacogenetics ...... 151 Pharmacogenomics and Drug Discovery ...... 152 Preclinical Prediction of Drug Effi cacy ...... 153 Pharmacogenomics and Clinical Trials ...... 154 Impact of Genetic Profi ling on Clinical Studies ...... 155 Limitations of the Pharmacogenomic-Based Clinical Trials ...... 156 Current Status and Future Prospects of Pharmacogenomics ...... 157 References ...... 158 6 Pharmacoproteomics ...... 159 Basics of Proteomics ...... 159 Proteomic Approaches to the Study of Pathophysiology of Diseases ...... 160 Single Cell Proteomics for Personalized Medicine ...... 161 Diseases Due to Misfolding of Proteins ...... 161 Therapies for Protein Misfolding ...... 162 Proteomic Technologies for Drug Discovery and Development ...... 163 Role of Reverse-Phase Protein Microarray in Drug Discovery ...... 164 Dynamic Proteomics for Targeting Disease Pathways ...... 164 Target Identifi cation and Validation ...... 164 Role of Proteomics in Clinical Drug Safety ...... 165 Toxicoproteomics ...... 165 Applications of Pharmacoproteomics in Personalized Medicine ...... 168 References ...... 168 7 Role of in Personalized Medicine ...... 169 Metabolomics and Metabonomics ...... 169 Metabolomics Bridges the Gap Between Genotype and Phenotype ...... 170 Metabolomics, Biomarkers and Personalized Medicine ...... 171 Urinary Profi ling by Capillary Electrophoresis ...... 172 Contents xvii

Lipid Profi ling ...... 173 Role of Metabolomics in Biomarker Identifi cation and Pattern Recognition ...... 173 Validation of Biomarkers in Large-Scale Human Metabolomics Studies ...... 174 Pharmacometabonomics ...... 174 Metabonomic Technologies for Toxicology Studies ...... 175 Metabonomics/Metabolomics and Personalized Nutrition ...... 176 References ...... 176 8 Non-genomic Factors in the Development of Personalized Medicine ...... 179 Introduction ...... 179 Circadian Rhythms and Personalized Medicine ...... 180 Environmental Factors in Disease ...... 181 Human Intestinal Microfl ora ...... 182 Metabolic Interactions of the Host and the Intestinal Microfl ora ...... 183 and Personalized Medicine ...... 183 Genetics vs. Epigenetics ...... 184 as a Basis for Personalized Medicine ...... 184 Contributions of Nanobiotechnology to Personalized Medicine ...... 185 Role of Nanobiotechnology in Molecular Diagnostics ...... 185 References ...... 187 9 Personalized Biological Therapies ...... 189 Introduction ...... 189 Recombinant Human Proteins ...... 189 Therapeutic Monoclonal Antibodies ...... 190 Cell Therapy ...... 190 Autologous Tissue and Cell Transplants ...... 191 Stem Cells ...... 191 Cloning and Personalized Cell Therapy...... 192 Use of Stem Cells for Drug Testing ...... 193 Gene Therapy ...... 193 Stem Cell-Based Personalized Gene Therapy for Cancer ...... 193 Personalized Vaccines ...... 194 Personalized Cancer Vaccines ...... 194 Antisense Therapy...... 194 RNA Interference ...... 195 MicroRNAs ...... 196 References ...... 197 10 Personalized Therapy of Cancer ...... 199 Introduction ...... 199 Challenges of Cancer Classifi cation ...... 199 Systems Biology of Cancer ...... 200 xviii Contents

Relationships of Technologies for Personalized Management of Cancer ...... 201 Impact of Molecular Diagnostics on the Management of Cancer ...... 202 A Universal NGS-Based Oncology Test System ...... 203 Analysis of RNA Splicing Events in Cancer ...... 203 Analysis of Chromosomal Alterations in Cancer Cells ...... 203 Cancer Classifi cation Using Microarrays ...... 204 Catalog of Cancer Genes for Personalized Therapy ...... 205 Circulating Cancer Cell Analysis for Personalizing Therapy ...... 206 Diagnosis of Cancer of an Unknown Primary ...... 207 Diagnostics for Detection of Minimal Residual Disease ...... 207 DNA Repair Biomarkers ...... 208 Fluorescent In Situ Hybridization ...... 208 Gene Expression Profi ling ...... 208 Isolation and Characterization of Circulating Cancer Cells ...... 211 Modulation of CYP450 Activity for Cancer Therapy ...... 211 NanoFlares for Detection of CTCs ...... 212 Pathway-Based Analysis of Cancer ...... 212 Quantum Dot-Based Test for DNA Methylation ...... 213 Role of Molecular Imaging in Personalized Therapy of Cancer ...... 214 Unraveling the Genetic Code of Cancer ...... 217 Cancer Prognosis ...... 217 Detection of Mutations for Risk Assessment and Prevention ...... 218 Hematological Cancer Risk Inferred from Blood DNA Sequence ...... 219 Impact of Biomarkers on Management of Cancer ...... 220 HER-2/neu Oncogene as a Biomarker for Cancer ...... 220 L-Asparaginase Treatment of Cancer Guided by a Biomarker ...... 220 Oncogene GOLPH3 as a Cancer Biomarker ...... 221 Predictive Biomarkers for Cancer ...... 221 Sequencing to Discover Biomarkers to Personalize Cancer Treatment ...... 222 VeraTag™ Assay System for Cancer Biomarkers ...... 223 Determination of Response to Therapy ...... 223 Biomarker-Based Assays for Predicting Response to Anticancer Therapeutics...... 223 Ex Vivo Testing of Tumor Biopsy for Chemotherapy Sensitivity ...... 224 Genomic Approaches to Predict Response to Anticancer Agents ...... 225 Non-genetic Factors for Variations in Response of Cancer Cells to Drugs ...... 227 Proteomic Analysis of Tumor Biopsies to Predict Response to Treatment ...... 228 Real-Time Apoptosis Monitoring ...... 228 Serum Nucleosomes as Indicators of Sensitivity to Chemotherapy ..... 229 Targeted Microbubbles to Tumors for Monitoring Anticancer Therapy ...... 230 Contents xix

PET Imaging for Determining Response to Chemotherapy ...... 230 Tissue Systems Biology Approach to Personalized Management of Cancer ...... 231 Molecular Diagnostics Combined with Cancer Therapeutics...... 232 Aptamers for Combined Diagnosis and Therapeutics of Cancer ...... 232 Combining Diagnosis and Therapy of Metastatic Cancer ...... 233 Detection and Destruction of CTCs with Nanoparticles and X-Rays ...... 234 Monoclonal Antibodies for Combining Diagnosis with Therapy of Cancer...... 234 Molecular Profi ling of Cancer ...... 235 Targeted Cancer Therapies ...... 235 Targeting Glycoproteins on Cell Surface ...... 235 Targeting Pathways in Cancer ...... 236 Targeted Personalized Anticancer Medicines in Clinical Use ...... 236 Immunotherapy of Cancer ...... 236 Functional Antibody-Based Therapies ...... 237 Immunotherapy of Dormant Cancer ...... 239 Personalized Cancer Vaccines ...... 240 Antigen-Specifi c Vaccines ...... 240 Tumor-Derived Vaccines...... 241 Patient-Specifi c Cell-Based Vaccines ...... 244 Adoptive Cell Therapy ...... 247 Personalized Peptide Cancer Vaccines ...... 250 Current Status and Future Prospects of Personalized Cancer Vaccines ...... 251 Personalized Radiation Therapy ...... 253 Use of Radiation Sensitivity Biomarkers to Personalized Radiotherapy ...... 255 Use of Imaging to Monitor Radioimmunotherapy of Non- Hodgkin Lymphoma ...... 255 Role of Nanobiotechnology in Personalized Management of Cancer ...... 256 Design of Future Personalized Cancer Therapies ...... 257 Personalized Therapy of Cancer Based on Cancer Stem Cells ...... 258 Role of Epigenetics in Development of Personalized Cancer Therapies...... 258 Selective Destruction of Cancer Cells While Sparing Normal Cells .... 259 Role of Oncoproteomics in Personalized Therapy of Cancer ...... 261 Cancer Tissue Proteomics ...... 261 Role of Sequencing in Personalized Therapy of Cancer...... 262 Pharmacogenomic-Based Chemotherapy ...... 264 Whole Genome Technology to Predict Drug Resistance ...... 264 Anticancer Drug Selection Based on Molecular Characteristics of Tumor ...... 264 xx Contents

Testing Microsatellite-Instability for Response to Chemotherapy ...... 265 Pharmacogenetics of Cancer Chemotherapy ...... 266 CYP 1A2 ...... 266 Thiopurine Methyltransferase ...... 267 Dihydropyrimidine Dehydrogenase ...... 267 UGT1A1 Test as Guide to Irinotecan Therapy ...... 268 Role of Computational Models in Personalized Anticancer Therapy ...... 269 A Computational Model of Kinetically Tailored Treatment ...... 269 Mathematical Modeling of Tumor Microenvironments ...... 270 Modeling Signaling Pathways to Reposition Anticancer Drugs ...... 270 Therapy Resistance in Cancer ...... 271 Mechanism of Therapy Resistance in Cancer ...... 271 Detection of Drug Resistance ...... 273 Management of Drug Resistance in Cancer ...... 274 Personalized Therapy of Cancer Metastases ...... 277 Personalized Management of Cancers of Various Organs ...... 278 Personalized Management of Brain Tumors ...... 278 Personalized Management of Breast Cancer ...... 292 Personalized Management of Ovarian Cancer ...... 318 Personalized Management of Head and Neck Cancer ...... 325 Personalized Management of Hematological Malignancies ...... 326 Personalized Management of Lymphomas ...... 334 Personalized Management of Gastrointestinal Cancer ...... 337 Personalized Management of Liver Cancer ...... 345 Personalized Management of Lung Cancer ...... 346 Personalized Management of Malignant Melanoma ...... 355 Personalized Management of Pancreatic Cancer ...... 358 Personalized Management of Prostate Cancer ...... 360 Personalized Management of Thyroid Cancer ...... 364 Future of Cancer Therapy ...... 364 Challenges for Developing Personalized Cancer Therapies ...... 365 Cancer Genome Atlas ...... 365 COLTHERES Consortium ...... 366 Computer and Imaging Technologies for Personalizing Cancer Treatment ...... 366 Genomic Cancer Care Alliance ...... 367 Integrated Genome-Wide Analysis of Cancer for Personalized Therapy ...... 367 International Cancer Genome Consortium ...... 368 National Cancer Institute of US ...... 369 PREDICT Consortium ...... 370 Quebec Clinical Research Organization in Cancer ...... 370 References ...... 371 Contents xxi

11 Personalized Management of Infectious Diseases ...... 383 Introduction ...... 383 Personalized Management of Bacterial Infections ...... 383 Bacterial Genomics and Sequencing ...... 383 Role of Rapid Molecular Diagnosis at Point of Care ...... 385 Personalized Vaccines Against Bacterial Infections ...... 385 Personalized Management of Sepsis ...... 386 Personalized Management of Tuberculosis ...... 386 Personalized Management of Viral Infections ...... 387 Personalized Approach to Management of HIV ...... 388 Personalized Treatment of Hepatitis B ...... 401 Personalized Treatment of Hepatitis C ...... 402 Personalized Management of Fungal Infections ...... 405 Personalized Management of Malaria ...... 406 Genomics of Malaria ...... 406 References ...... 407 12 Personalized Management of Neurological Disorders ...... 409 Introduction ...... 409 Neurogenomics ...... 409 Applications of Neurogenomics in Neurological Disorders ...... 410 Impact of Neurogenomics on the Development of Personalized Neurology ...... 412 Epigenomics/Epigenetics ...... 412 Neuroproteomics ...... 413 Applications of Neuroproteomics for Study of the Nervous System ...... 413 CSF Tests Based on Proteomics ...... 414 Diagnosis of Neurologic Disorders by Examination of Proteins in the Blood ...... 414 Role of Proteomics in Neuropharmacology ...... 416 Neurometabolomics ...... 417 Diagnosis-Guided Therapies for Neurological Disorders ...... 417 Personalized Biological Therapies for Neurological Disorders ...... 417 Personalized Management of Alzheimer Disease ...... 418 Introduction to Alzheimer Disease ...... 418 Diagnosis of AD ...... 418 Genomic Basis of Personalized Approach to Alzheimer Disease ...... 420 Prospects for the Future Management of AD ...... 421 Personalized Management of Parkinson Disease ...... 421 Genomic Basis of Personalized Approach to Parkinson Disease ...... 421 Role of Pharmacogenetics in Personalizing Therapy of PD ...... 423 Discovery of Subgroup-Selective Drug Targets in PD ...... 423 Personalized Cell Therapy for PD ...... 424 xxii Contents

Personalized Management of Huntington’s Disease ...... 424 Genomics of Huntington Disease ...... 424 Genetic Testing for HD ...... 425 Personalized Cell Therapy for Huntington Disease ...... 425 Personalized Management of Epilepsy ...... 425 Biomarkers of Epilepsy ...... 426 Genetics/Genomics of Epilepsy ...... 427 Choice of the Right Antiepileptic Drug ...... 429 Pharmacogenomics of Epilepsy ...... 429 Pharmacogenetics of Epilepsy ...... 431 Drug Resistance in Epilepsy ...... 431 An Algorithm for Personalized Management of Epilepsy ...... 433 Future Prospects for Management of Epilepsy ...... 433 Personalized Management of Migraine ...... 435 Pharmacogenomics of Migraine ...... 435 Individualization of Use of Triptans for Migraine ...... 436 Multitarget Therapeutics for Personalized Treatment of Headache ...... 436 Personalized Management of Stroke ...... 437 Application of Proteomics for Personalizing Stroke Management ...... 437 Brain Imaging in Trials of Restorative Therapies for Stroke ...... 438 Decisions for Evacuation of Intracerebral Hemorrhage ...... 438 Decisions for Revascularization Procedures in Chronic Post- stroke Stage ...... 438 Personalized Treatment of Multiple Sclerosis ...... 440 Genomics of Multiple Sclerosis ...... 441 Pharmacogenetic Approach to Management of Multiple Sclerosis ...... 441 Immunopathological Patterns of Demyelination for Assessing Therapy ...... 442 Personalizing Mitoxantrone Therapy of Multiple Sclerosis ...... 442 Personalized Cell Therapy of Multiple Sclerosis ...... 443 Pharmacogenomics of IFN-β Therapy in Multiple Sclerosis...... 444 T Cell-Based Personalized Vaccine for MS ...... 445 Personalized Management of Pain ...... 446 Genetic Factors in Response to Pain ...... 446 Genetic Mutations with Loss of Pain ...... 448 Pharmacogenetics/Pharmacogenomics of Pain ...... 448 Mechanism-Specifi c Management of Pain ...... 451 Preoperative Testing to Tailor Postoperative Analgesic Requirements ...... 451 Personalized Analgesics ...... 452 Signature of Pain on Brain Imaging ...... 452 Concluding Remarks on Personalized Management of Pain ...... 452 Personalized Management of Traumatic Brain Injury ...... 454 Molecular Basis of Management of Traumatic Brain Injury ...... 454 Contents xxiii

Personalized Management of Sleep Disorders ...... 454 Personalized Therapy of Insomnia ...... 454 Personalized Approach to Chronic Fatigue Syndrome ...... 455 Personalized Approach to Ataxias ...... 455 Future Prospects of Personalized Neurology ...... 456 References ...... 456 13 Personalized Management of Psychiatric Disorders ...... 461 Introduction ...... 461 Psychopharmacogenetics/Psychopharmacodynamics ...... 462 Serotonin Genes ...... 462 Calcium Channel Gene ...... 463 Dopamine Receptor Genes ...... 463 Methylenetetrahydrofolate Reductase ...... 464 GeneSight Tests for Individualized Therapy of Psychiatric Disorders ...... 464 Personalized Antipsychotic Therapy ...... 465 Personalized Antidepressant Therapy ...... 467 Personalized Management of ADHD ...... 472 Genotype and Response to Methylphenidate in Children with ADHD ...... 473 Pharmaco-EEG for Personalized Treatment of ADHD ...... 473 Personalized Approach to Addiction ...... 473 Pharmacogenetics of Drug Addiction ...... 473 Genetic Polymorphism and Management of Alcoholism ...... 474 Personalized Therapy for Smoking Cessation ...... 475 Future Prospects of Personalized Psychiatry ...... 476 References ...... 477 14 Personalized Management of Cardiovascular Disorders ...... 479 Introduction ...... 479 Cardiogenomics ...... 479 Role of Diagnostics in Personalized Management of Cardiovascular Disease ...... 482 Cardiovascular Disorders with a Genetic Component ...... 482 Biomarkers and Personalized Management of Cardiovascular Disorders ...... 488 Pharmacogenomics of Cardiovascular Disorders ...... 488 Modifying the Genetic Risk for Myocardial Infarction ...... 489 Personalized Management of Chronic Myocardial Ischemia ...... 489 Management of Heart Failure ...... 490 Management of Hypertension ...... 492 Pharmacogenetics of Lipid-Lowering Therapies ...... 498 Thrombotic Disorders ...... 502 Nanobiotechnology-Based Personalized Therapy of Cardiovascular Diseases ...... 505 xxiv Contents

Project euHeart for Personalized Management of Heart Disease ...... 506 Concluding Remarks on Personalized Management of Cardiovascular Diseases ...... 507 References ...... 507 15 Personalized Management of Pulmonary Disorders ...... 511 Introduction ...... 511 Role of Genetic Ancestory in Lung Function ...... 511 Biomarkers of Pulmonary Disorders ...... 512 Biomarkers of Infl ammation and Lung Function in the Elderly ...... 513 Biomarkers of Oxidative Stress in Lung Diseases ...... 513 Biomarkers of Community-Acquired Pneumonia ...... 513 Personalized Therapy of Asthma ...... 515 Biomarkers of Asthma ...... 515 Genotyping in Asthma ...... 519 Lebrikizumab for Personalized Treatment of Asthma ...... 520 Personalized Therapy of Chronic Obstructive Pulmonary Disease ...... 521 Biomarkers of COPD ...... 521 Gene Expression Studies of Lung Tissue in COPD ...... 523 Prognosis of COPD ...... 524 Management of COPD ...... 524 Personalized Management of Interstitial Lung Disease ...... 525 Biomarkers of Interstitial Lung Disease ...... 525 Developing Personalized Therapies for Interstitial Lung Disease ...... 526 References ...... 527 16 Personalized Management of Genetic Disorders ...... 529 Introduction ...... 529 Molecular Diagnosis of Genetic Disorders ...... 529 Molecular Diagnostic Technologies ...... 530 Biomarkers for Genetic Disorders ...... 534 Biomarkers for Down’s Syndrome ...... 534 Biomarkers for Muscular Dystrophy ...... 535 Biomarkers of Phenylketonuria ...... 536 Genetic Biomarkers for Psoriasis ...... 536 Biomarkers of Lysosomal Storage Disorders ...... 537 Sequencing in Genetic Disorders ...... 538 DNA Sequencing for Prenatal Disorders ...... 539 Study of Rare Variants in Pinpointing Disease-Causing Genes ...... 542 Personalized Cell and Gene Therapies of Genetic Disorders ...... 543 Personalized Stem Cell Transplant for Sickle Cell Anemia...... 543 Hurler Syndrome ...... 544 Personalized Gene Therapy of Duchenne Muscular Dystrophy ...... 544 Personalized Treatment of Cystic Fibrosis ...... 547 Current Management of CF ...... 547 Contents xxv

Personalizing New Therapies for CF ...... 548 Gene Therapy and Pharmacogenomic Approach to CF ...... 548 References ...... 548 17 Personalized Approaches to Immune Disorders ...... 551 Introduction ...... 551 Personalized Approaches in Immunology ...... 552 Pharmacogenetics and Pharmacogenomics of Immunosuppression ...... 552 Personalized Management of Patients with Lupus Erythematosus ...... 553 Personalized Therapy of Rheumatoid Arthritis ...... 554 Genetics and Epigenetic Aspects of Rheumatoid Arthritis ...... 554 Variations in the Effectiveness of Various Treatments of RA ...... 555 Biomarkers for Personalizing Therapy of Rheumatoid Arthritis ...... 556 DIATSTAT™ Anti-cyclic Citrullinated Peptides in Rheumatoid Arthritis...... 557 Personalization of COX-2 Inhibitor Therapy...... 557 Personalization of Infl iximab Therapy ...... 557 Personalized Therapy of RA Guided by Anti-citrullinated Protein Antibodies ...... 558 Personalized Approaches to Improve Organ Transplantation ...... 558 Personalization of Kidney Transplantation ...... 558 Personalization of Cardiac Transplantation ...... 559 Prediction of Rejection for Personalizing Anti-rejection Treatment ...... 560 Personalized Immunosuppressant Therapy in Organ Transplants ...... 560 Role of Immunological Biomarkers in Monitoring Grafted Patients ...... 561 Improved Matching of Blood Transfusion ...... 563 References ...... 563 18 Personalized Approaches to Miscellaneous Problems in Healthcare ...... 565 Personalized Management of Diabetes ...... 565 Personalized Management of Gastrointestinal Disorders ...... 566 Infl ammatory Bowel Disease ...... 566 Personalized Management of Lactose Intolerance ...... 568 Personalized Geriatrics ...... 568 Chronological vs Biological Age ...... 568 Pharmacogenetics and Adverse Drug Reactions ...... 569 Personalized Management of Skin Disorders ...... 569 Genetic Testing for Personalized Skin Care ...... 569 Management of Hair Loss Based on Genetic Testing ...... 570 Personalized Preventive Medicine ...... 570 Female Sexual Dysfunction ...... 571 Hormone Replacement Therapy in Women ...... 571 xxvi Contents

Personalized Management of Osteoporosis ...... 572 Personalized Management of Renal Disease ...... 573 Personalized Care of Trauma Patients ...... 573 Personalized Medical Care of Astronauts During Space Flights ...... 574 References ...... 575 19 Personalized Non-pharmacological Therapies ...... 577 Introduction ...... 577 Acupuncture ...... 577 Personalized Acupuncture Therapy ...... 578 Personalized Hyperbaric Oxygen Therapy ...... 578 Personalized Nutrition ...... 579 Nutrigenomics ...... 580 Nutrition and Proteomics ...... 583 Personalized Diet Prescription ...... 583 Personalized Physical Exercise ...... 584 Variations in Response to Aerobic Exercise ...... 584 Variations in Exercise-Induced Muscle Hypertrophy and Strength ...... 585 Personalized Surgery...... 585 References ...... 586 20 Development of Personalized Medicine ...... 589 Introduction ...... 589 Players in the Development of Personalized Medicine ...... 589 Personalized Medicine Coalition ...... 590 Role of Pharmaceutical Industry ...... 591 Personalized Drug Discovery ...... 592 Personalized Approach to Clinical Trials ...... 592 Role of Drug Delivery in Personalized Medicine ...... 595 Repositioning of Drugs for Personalized Medicine ...... 595 Production and Distribution of Personalized Medicines ...... 596 Role of Biotechnology Companies ...... 597 Role of Life Sciences Industries ...... 597 Role of the Clinical Laboratories ...... 598 Role of Molecular Imaging in Personalized Medicine ...... 598 Role of the US Government and Agencies in Personalized Medicine ...... 603 Department of Health and Human Services and Personalized Medicine ...... 604 Agency for Healthcare Research and Quality ...... 605 Comparative Effectiveness Research ...... 606 Role of the US Government Agencies in Personalized Medicine ...... 608 Role of Academic Institutions in the US ...... 614 Baylor College of Medicine ...... 614 Coriell Personalized Medicine Collaborative™ ...... 615 Delaware Valley Personalized Medicine Project ...... 616 Duke University Medical Center and Genomic Medicine ...... 616 Contents xxvii

Ignite Institute ...... 617 Indiana University Institute for Personalized Medicine ...... 618 Institute of Medicine’s Role in Personalized Medicine ...... 619 Jackson Laboratory for Genomic Medicine ...... 619 Johns Hopkins Center for Personalized Cancer Medicine Research ...... 620 Mayo Clinic’s Centers for Individualized Medicine ...... 620 Mt. Sinai Medical Center’s Personalized Medicine Research Program ...... 621 New York Genome Center ...... 622 P4 Medicine Institute ...... 622 Personalized Medicine Partnership of Florida ...... 623 Partners Personalized Medicine at Massachusetts General Hospital ...... 623 Personalized Oncology at Oregon Health & Science University ...... 624 Southeast Nebraska Cancer Center’s Personalized Medicine Network ...... 624 Stanford Center for Genomics and Personalized Medicine ...... 625 UAB-HudsonAlpha Center for Genomic Medicine ...... 626 University of Colorado’s Center for Personalized Medicine ...... 626 UNC Institute for Pharmacogenomics and Individualized Therapy ...... 627 Wisconsin Genomics Initiative ...... 627 Role of Healthcare Organizations ...... 628 Role of the Medical Profession ...... 628 The American Medical Association and Personalized Medicine ...... 629 Medical Education ...... 629 Off-Label Prescribing and Personalized Medicine ...... 630 Role of Patients ...... 630 Public Attitude Towards Personalized Medicine ...... 631 Role of Genetic Banking Systems and Databases ...... 632 Role of Biobanks in Development of Personalized Medicine ...... 632 CARTaGENE for Biobanks in Canada ...... 634 Role of Bioinformatics in Development of Personalized Medicine ...... 635 Exploration of Disease-Gene Relationship ...... 636 Biosimulation Techniques for Developing Personalized Medicine ...... 636 Health Information Management ...... 637 Electronic Health Records ...... 637 Personalized Prognosis of Disease ...... 642 Global Scope of Personalized Medicine ...... 643 Global Alliance for Genomics and Health ...... 643 Personalized Medicine in Canada ...... 643 Personalized Medicine in the EU ...... 647 Personalized Medicine in Israel ...... 650 Personalized Medicine in the Developing Countries ...... 650 xxviii Contents

Advantages of Personalized Medicine ...... 651 Limitations of Personalized Medicine ...... 652 References ...... 654 21 Ethical Aspects of Personalized Medicine ...... 655 Introduction to Ethical Issues ...... 655 Ethical Issues of Pharmacogenetics ...... 655 Ethical Aspects of Genetic Information ...... 656 Ethical Issues of Whole Genome Analysis ...... 656 Ethical Aspects of Direct-to-Consumer Genetic Services ...... 657 Privacy Issues in Personalized Medicine ...... 658 Genetic Information Nondiscrimination Act in the US ...... 659 Genotype-Specifi c Clinical Trials ...... 659 Social Issues in Personalized Medicine ...... 660 Race and Personalized Medicine ...... 660 Gene Patents and Personalized Medicine ...... 663 References ...... 664 22 Regulatory Aspects of Personalized Medicine ...... 665 Introduction ...... 665 FDA and Personalized Medicine ...... 666 Regulatory Aspects of Pharmacogenetics ...... 666 FDA and Pharmacogenomics ...... 667 FDA and Validation of Biomarkers ...... 669 FDA and ...... 671 FDA Regulation of Multivariate Index Assays ...... 672 Evaluation of Companion Diagnostics/Therapeutic ...... 674 CLSI Guidelines for RNA Controls in Gene Expression Assays ...... 676 Regulation of Direct-to-Consumer Genetic Testing ...... 676 Need for Regulatory Oversight of DTC ...... 677 References ...... 680 23 Economics of Personalized Medicine ...... 681 Introduction ...... 681 Perceived Financial Concerns ...... 681 Personalized Medicine and Orphan Drug Syndrome ...... 682 Commercial Aspects of Pharmacogenomics ...... 682 Cost of DNA Testing ...... 682 Lowering the Cost of Sequencing the Human Genome ...... 683 Cost of Genotyping ...... 684 Cost of Pharmacogenomics-Based Clinical Trials ...... 685 Personalized Medicine and the Rising Healthcare Costs in the US ...... 686 Genetic Testing and Cost of Healthcare ...... 687 Reducing Healthcare Costs by Combining Diagnostics with Therapeutics ...... 687 Costs of Pharmacogenetic Testing ...... 688 Contents xxix

Pharmacogenetics to Reduce the Cost Incurred by Adverse Drug Reactions ...... 688 Cost Effectiveness of HIV Genotyping in Treatment of AIDS ...... 689 Cost-Effectiveness of Warfarin Pharmacogenomics ...... 690 Cost-Benefi t Analysis of KRAS and BRAF Screening in CRC ...... 690 Lowering the High Costs of Cancer Chemotherapy ...... 691 Concluding Remarks on the Economics of Personalized Medicine ...... 691 References ...... 692 24 Future of Personalized Medicine ...... 693 Introduction ...... 693 Ongoing Studies ...... 693 Personal Genome Project ...... 693 Genome-Wide Association Studies ...... 694 The 1000 Genomes Project ...... 695 Genomics of Aging in a Genetically Homogeneous Population ...... 696 Translational Science and Personalized Medicine ...... 696 Translation of Genomic Research into Genetic Testing for Healthcare ...... 697 Long-Term Behavioral Effects of Personal Genetic Testing ...... 698 Personalized Predictive Medicine ...... 698 Connected Health and Personalized Medicine ...... 699 Drivers for the Development of Personalized Medicine ...... 699 Evolution of Medicine as a Driver for Personalized Therapy Markets ...... 699 Collaboration Between the Industry and the Academia ...... 700 Opportunities and Challenges of Personalized Medicine ...... 701 Prospects and Limitations of Genetic Testing ...... 701 Genetic Testing and Concerns About Equality of Healthcare ...... 703 Pharmacotyping ...... 703 Comparative-Effectiveness Research and Personalized Medicine ...... 704 Medicine in the Year 2025 ...... 704 Concluding Remarks About the Future of Personalized Medicine ...... 706 References ...... 708

Index ...... 709

List of Figures

Fig. 1.1 Relation of personalized medicine to other technologies ...... 20 Fig. 1.2 Relation of systems pharmacology to personalized medicine ...... 27 Fig. 1.3 Integration of technologies for the development of personalized medicine ...... 30 Fig. 2.1 Role of sequencing in the development of personalized medicine ...... 41 Fig. 2.2 Role of biochip/microarray technology in personalized medicine ...... 45 Fig. 2.3 Application of biochips/microarrays in personalized therapy ...... 46 Fig. 2.4 Role of CYP450 genotyping in development of personalized medicine ...... 50 Fig. 2.5 Basic principle of a biosensor. The compound of interest (black circles) in a mixture of substances specifi cally interacts with the biological sensing part of the sensor. The resulting biological signal is converted into a physical signal (e.g., electric or optical) by a transducer. Substances which are not capable of interacting with the biological component (hollow circles) will not produce any signal ...... 52 Fig. 2.6 Role of SNPs in personalized medicine ...... 59 Fig. 2.7 The central role of spectrometry in proteomics ...... 75 Fig. 3.1 Impact of biomarkers on personalized medicine ...... 92 Fig. 4.1 Pharmacogenetics as a link between genotype and phenotype ...... 100 Fig. 4.2 Role of pharmacogenetic technologies in personalized medicine ...... 100 Fig. 5.1 Impact of new technologies at various stages of the drug discovery process ...... 152 Fig. 5.2 Steps in the application of pharmacogenomics in clinical trials ...... 154

xxxi xxxii List of Figures

Fig. 9.1 Role RNAi in development of personalized medicine ...... 196 Fig. 10.1 Relationships of technologies for personalized management of cancer ...... 201 Fig. 10.2 Role of nanobiotechnology in personalized management of cancer ...... 256 Fig. 11.1 An integrated approach to viral diseases ...... 388 Fig. 11.2 Mode of action of some current anti-HIV drugs ...... 393 Fig. 11.3 Workfl ow of genotypic resistance analysis for personalized HIV therapy. Workfl ow of current-day genotypic resistance analysis. The process begins by detecting the viral load (2) in a patient (1). In the case of anticipated therapy change the viral genome is sequenced from the patient’s blood serum (3). Interpretations of the viral genome sequence is effected either manually using a mutation table (4a), or via a rules-based system (4b), or with a statistical model derived from clinical resistance data (4c). The interpretation results in a resistance profi le (5) that is qualitative in the fi rst two cases and quantitative when using statistical models. The physician uses this profi le to select a therapy (9). In doing so, additional information on the patient is also taken into account (patient history, habits, drug side effects, etc. (6). Therapy prediction engines (7) can assist this process by a quantitative analysis that yields a list of therapies ranked by their likelihood of success (8) (Source: Lengauer et al. 2014) ...... 399 Fig. 12.1 Relationships of neurogenomics with other omics ...... 410 Fig. 12.2 Role of neurogenomics in the development of personalized neurology ...... 411 Fig. 12.3 Scheme of iPSCs for personalized cell therapy of Parkinson disease ...... 424 Fig. 12.4 An algorithm for personalized management of epilepsy ...... 434 Fig. 12.5 Essential components of personalized management of pain ...... 447 Fig. 12.6 Genetic & non-genetic factors affecting effi cacy and side effects of opioids (Modifi ed from Sadhasivam et al. 2014) ...... 450 Fig. 12.7 An algorithm for personalized management of pain ...... 453 Fig. 14.1 A scheme of personalized approach to management of hypertension ...... 499 List of Figures xxxiii

Fig. 23.1 Cost of sequencing per genome (DNA sequencing costs: data from the NHGRI Genome Sequencing Program. http://www.genome.gov/sequencingcosts (accessed on 8 Jan 2015)) ...... 684 Fig. 24.1 Evolution of personalized medicine as a market driver ...... 701

List of Tables

Table 1.1 Selected terms relevant to the concept of personalized medicine ...... 2 Table 1.2 Landmarks in the historical development of personalized medicine ...... 4 Table 1.3 Genetic variations in the human genome ...... 10 Table 2.1 Molecular diagnostic technologies used for personalized medicine...... 36 Table 2.2 Applications of biochip technology relevant to personalized medicine ...... 46 Table 2.3 Technologies for SNP analysis ...... 63 Table 2.4 Comparison of proteomic and genomic approaches in personalized medicine ...... 76 Table 2.5 Selected methods for gene expression profi ling ...... 77 Table 2.6 Drugs requiring biomarker/companion diagnostic information in the label ...... 83 Table 2.7 Applications of point-of-care diagnosis ...... 85 Table 4.1 Enzymes relevant to drug metabolism ...... 103 Table 4.2 Examples of mutation of the enzyme CYP450 ...... 104 Table 4.3 Frequency distribution of drugs metabolized by major isoforms of CYP450 ...... 104 Table 4.4 Commonly prescribed medications, which are metabolized by CYP2D6 ...... 104 Table 4.5 Polymorphisms in drug target genes that can infl uence drug response ...... 112 Table 4.6 Effect of genetic polymorphisms on disease response to drugs ...... 113 Table 4.7 Examples of genetically determined adverse reactions to drugs ...... 118 Table 4.8 Examples of genotyping and phenotyping in some diseases ...... 129 Table 4.9 Pharmacogenomic biomarkers in drug labeling ...... 135

xxxv xxxvi List of Tables

Table 5.1 Role of pharmacogenomics in variable therapy targets ...... 150 Table 5.2 Pharmacogenetic vs. pharmacogenomic studies ...... 151 Table 5.3 Role of pharmacogenomics in clinical trials ...... 154 Table 5.4 Examples of pharmacogenomics-based clinical studies ...... 155 Table 10.1 Factors that drive the development of personalized therapy in cancer ...... 200 Table 10.2 Impact of molecular diagnostics on the management of cancer ...... 202 Table 10.3 Marketed anticancer personalized medicines ...... 237 Table 10.4 Clinical trials of personalized cancer vaccines ...... 252 Table 12.1 Applications of genomics in neurology ...... 411 Table 12.2 Disease-specifi c proteins in CSF of patients with neurologic disorders ...... 415 Table 12.3 Neurodegenerative diseases with underlying protein abnormalities...... 416 Table 12.4 Biomarkers of epilepsy ...... 426 Table 12.5 Infl uence of gene polymorphisms on effi cacy of antiepileptic drugs ...... 430 Table 12.6 Role of cell therapy in management of stroke according to stage ...... 439 Table 12.7 Gene expression as biomarker of response to IFN-β in multiple sclerosis ...... 446 Table 12.8 P450 isoforms in the metabolism of drugs used in the management of pain ...... 449 Table 12.9 Personalized management of neuropathic pain based on mechanism ...... 453 Table 13.1 Enzymes that metabolize antipsychotics ...... 466 Table 13.2 Enzymes that metabolize antidepressants ...... 468 Table 13.3 Biomarkers of response to antidepressant treatment ...... 469 Table 13.4 Genetic infl uences on pharmacotherapy of alcoholism ...... 475 Table 14.1 Gene polymorphisms relevant to cardiovascular disease management ...... 481 Table 14.2 Genes that cause cardiovascular diseases ...... 483 Table 15.1 Biomarkers of pulmonary diseases ...... 512 Table 16.1 Mutation detection technologies ...... 534 Table 16.2 Gene therapy approaches to Duchenne muscular dystrophy ...... 545 Table 20.1 Players in the development of personalized medicine ...... 590 Table 20.2 Members of the personalized medicine coalition ...... 591 Table 20.3 Role of bioinformatics in the development of personalized medicine ...... 635 List of Tables xxxvii

Table 20.4 Advantages of personalized medicine for the biopharmaceutical industry ...... 651 Table 20.5 Advantages of personalized medicine for the patients ...... 652 Table 20.6 Advantages of personalized medicine for the physicians ...... 652 Table 20.7 Advantages of personalized medicine for the healthcare providers ...... 652 Table 20.8 Limitations of personalized medicine ...... 653 Table 22.1 Drugs with genetic information in their labels ...... 670 Table 24.1 Methods of translational science that are relevant to personalized medicine ...... 697 Table 24.2 Drivers for the development of personalized medicine ...... 700

Abbreviations

ACE Angiotensin-converting enzyme ADME Adsorption, distribution, metabolism, excretion ADR Adverse drug reaction CE Capillary electrophoresis CF Cystic fi brosis CML Chronic myeloid leukemia CT Computerized tomography CRADA Cooperative Research & Development Agreement CYP Cytochrome P DARPA Defense Advanced Research Projects Agency DHPLC Denaturing high performance liquid chromatography DNA Deoxyribonucleic acid DR Dopamine receptor dsDNA Double-stranded DNA eNOS Endothelial nitric oxide synthase EPOE Apolipoprotein E HER Electronic health records FDA Food and Drug Administration (USA) FISH Fluorescent in situ hybridization GFP Green fl uorescent protein HCV Hepatitis C virus HER-2 Human epidermal growth factor receptor-2 HIV Human immunodefi ciency virus IL Interleukin JAK Janus kinase MAb Monoclonal antibody MALDI-TOF Matrix Assisted Laser Desorption Ionization Time of Flight MDR Multidrug resistance protein MHC Major histocompatibility complex MRI Magnetic resonance imaging mRNA Messenger RNA

xxxix xl Abbreviations

MS mtDNA Mitochondrial DNA MTHFR Methylenetetrahydrofolate reductase NCI National Cancer Institute NGS Next generation sequencing PARP Poly (ADP-ribose) polymerase PCR Polymerase chain reaction PET Positron emission tomography PNA Peptide nucleic acid POC Point-of-care RCAT Rolling circle amplifi cation technology RFLP Restriction fragment length polymorphism RNA Ribonucleic acid SBIR Small Business Innovation Research SELDI Surface-enhanced laser desorption/ionization SNP Single nucleotide polymorphism STAT Signal transducer and activator of transcription TDM Therapeutic drug monitoring TKI Tyrosine kinase inhibitor TNF Tumor necrosis factor TPMT Thiopurine methyltransferase WGA Whole genome association WGS Whole genome sequence ZFP Zinc fi nger proteins