Textbook of Personalized Medicine

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Kewal K. Jain

Textbook of Personalized
Medicine
Kewal K. Jain
Jain PharmaBiotech
Blaesiring 7
4057 Basel
Switzerland
[email protected]

ISBN 978-1-4419-0768-4 e-ISBN 978-1-4419-0769-1

DOI 10.1007/978-1-4419-0769-1
Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2009928619

© Springer Science+Business Media, LLC 2009

All rights reserved. This work may not be translated or copied in whole or in part without the written
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Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

Dedicated to Barack Obama,
President of United States who introduced
the bill titled “Genomics and Personalized
Medicine Act of 2006” in the US
Senate in 2006
Preface

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 medi-
cine, of which molecular diagnostics has the biggest share, are mentioned briefly
and appropriate references are given for further information. Commercial aspects
are discussed briefly 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 latest version of the first 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 selected studies done during this
period in a readable format for the physicians and scientists. It is hoped that physi-
cians, pharmacists, scientists, and interested lay readers with basic scientific knowl-
edge will find this book useful.
Basel, Switzerland K.K. Jain MD

vii
Contents

Preface............................................................................................................... vii

1 Basics of Personalized Medicine............................................................... 1

Definition of Personalized Medicine........................................................... 1
History of Medical Concepts Relevant to Personalized Medicine.............. 3
Molecular Biological Basis of Personalized Medicine................................ 5
The Human Genome................................................................................ 6
Chromosomes.......................................................................................... 6
Genes........................................................................................................ 7
The Genetic Code................................................................................ 7
Gene Expression.................................................................................. 8
DNA Sequences and Structure............................................................. 8
Single Nucleotide Polymorphisms....................................................... 9
Genotype and Haplotypes.................................................................... 9
Genetic Variations in the Human Genome............................................... 9
Insertions and Deletions in the Human Genome................................. 10
Large Scale Variation in Human Genome........................................... 11
Variation in Copy Number in the Human Genome.............................. 11
Structural Variants in the Human Genome.......................................... 12
Mapping and Sequencing of Structural Variants from
Human Genomes.............................................................................. 13
1,000 Genomes Project........................................................................ 14
Human Variome Project....................................................................... 15
Basics Technologies for Developing Personalized Medicine...................... 15
Definitions of Technologies Relevant to Personalized Medicine............ 15
Problems with the ICH Definitions of Pharmacogenomics
and Pharmacogenetics.......................................................................... 16
Relationship of Various Technologies to Personalized Medicine............ 16
Conventional Medicine vs. Personalized Medicine..................................... 17
Genetic Basis of Personalized Medicine...................................................... 18
Genetic Medicine..................................................................................... 18
Human Disease and Genes....................................................................... 18

ix
x Contents

Genetic and Environmental Interactions in Etiology

of Human Diseases.............................................................................. 19
Mass Analysis of DNA from Whole Populations.................................... 19
Role of Genetics in Development of Personalized Medicines................. 20
Genetic Databases................................................................................ 20
Genetic Epidemiology......................................................................... 21
Limitations of Medical Genetics and Future Prospects....................... 22
Genetics vs. Epigenetics...................................................................... 22
Role of Systems Biology in Personalized Medicine.................................... 22
Systems Pharmacology............................................................................ 24
Systems Medicine.................................................................................... 24
A Personalized Approach to Environmental Factors in Disease................. 25
Reclassification of Diseases......................................................................... 26
Summary...................................................................................................... 27

2 Molecular Diagnostics as Basis of Personalized Medicine..................... 29

Introduction.................................................................................................. 29
Molecular Diagnostic Technologies............................................................ 29
DNA Sequencing......................................................................................... 30
Biochips and Microarrays............................................................................ 30
DNA Biochip Technology for Developing Personalized Medicine......... 30
Role of Protein Biochips in Personalized Medicine................................ 34
Cytogenetics................................................................................................. 35
Molecular Cytogenetics as Basis for Personalized Medicine.................. 35
Cytomics as a Basis for Personalized Medicine...................................... 36
SNP Genotyping.......................................................................................... 37
Technologies for SNP Analysis............................................................... 37
Applications of SNPs Relevant to Personalized Medicine...................... 37
Concluding Remarks on SNP Genotyping.............................................. 39
Haplotyping.................................................................................................. 40
HapMap Project....................................................................................... 41
Predicting Drug Response with HapMap................................................ 42
Nanodiagnostics for Personalized Medicine................................................ 42
Cantilevers for Personalized Medical Diagnostics.................................. 43
Nanopore-Based Technology for Single Molecule Identification........... 44
Application of Proteomics in Molecular Diagnosis..................................... 44
Comparison of Proteomic and Genomic Approaches in
Personalized Medicine......................................................................... 44
Gene Expression Profiling........................................................................... 45
DNA Microarrays for Gene Expression Studies...................................... 46
Analysis of Single-Cell Gene Expression................................................ 47
Gene Expression Profiling Based on Alternative RNA Splicing............. 47
Molecular Imaging and Personalized Medicine.......................................... 48
Monitoring In Vivo Gene Expression by Molecular Imaging................. 49
Glycomics-Based Diagnostics..................................................................... 49
Contents xi

Combination of Diagnostics and Therapeutics............................................ 50

Point-of-Care Diagnosis............................................................................... 50
Point-of-Care Diagnosis of Infections..................................................... 52
Advantages vs. Disadvantages of Point-of-Care Diagnosis..................... 52
Future Prospects of Point-of-Care Diagnosis.......................................... 53
Genetic Testing for Disease Predisposition................................................. 53
Personal Genetic Service......................................................................... 54
Role of Diagnostics in Integrated Healthcare.............................................. 54
Concept of Integrated Healthcare............................................................ 54
Components of Integrated Healthcare..................................................... 55
Screening.............................................................................................. 55
Disease Prediction................................................................................ 55
Early Diagnosis.................................................................................... 55
Prevention............................................................................................ 56
Therapy Based on Molecular Diagnosis.............................................. 56
Monitoring of Therapy......................................................................... 56
Advantages and Limitations of Integrated Healthcare............................. 56
Future of Molecular Diagnostics in Personalized Medicine........................ 57
Summary...................................................................................................... 57

3 Role of Biomarkers in Personalized Medicine........................................ 59

Introduction.................................................................................................. 59
Technologies for Discovery of Biomarkers................................................. 60
Systems Biology Approach to Biomarker Identification......................... 60
Epigenomic Technologies........................................................................ 60
Discovery of Methylation Biomarkers................................................. 62
Proteomic Strategies for Biomarker Identification.................................. 62
Proteomic Technologies for Detection of Biomarkers
in Body Fluids.................................................................................. 63
Biomarkers for Diagnostics......................................................................... 63
Biomarkers for Drug Development.............................................................. 64
Use of Biomarkers for Developing MAb Therapy in Oncology.............. 64
Biobanking, Biomarkers and Personalized Medicine.................................. 65
Expression Signatures as Diagnostic/Prognostic Tools............................... 66
Biomarkers for Monitoring Response to Therapy....................................... 66
Drug Rescue by Biomarker-Based Personalized Medicine......................... 67
Future Role of Biomarkers in Personalized Medicine................................. 68
Summary...................................................................................................... 68

4 Pharmacogenetics...................................................................................... 69
Basics of Pharmacogenetics......................................................................... 69
Role of Molecular Diagnostics in Pharmacogenetics.................................. 70
Role of Pharmacogenetics in Pharmaceutical Industry............................... 71
Study of the Drug Metabolism and Pharmacological Effects.................. 71
Causes of Variations in Drug Metabolism............................................... 72
xii Contents

Enzymes Relevant to Drug Metabolism.................................................. 72

Pharmacogenetics of Phase I Metabolism............................................... 73
Cyp450................................................................................................. 73
P450 CYP 2D6 Inhibition by Selective Serotonin Reuptake
Inhibitors (SSRIs)............................................................................ 75
Cytochrome P450 Polymorphisms and Response to Clopidogrel....... 76
Lansoprazole and Cytochrome P450................................................... 76
Glucose-6-Phosphate Dehydrogenase................................................. 77
Pharmacogenetics of Phase II Metabolism.............................................. 78
N-Acetyltransferase............................................................................. 78
Uridine Diphosphate-Glucuronosyltransferase.................................... 79
Measurement of CYP Isoforms............................................................... 79
Polymorphism of Drug Transporters....................................................... 80
Genetic Variation in Drug Targets........................................................... 81
Polymorphisms of Kinase Genes......................................................... 82
Effect of Genetic Polymorphisms on Response of Disease to Drugs...... 82
Ethnic Differences in Drug Metabolism.................................................. 83
Gender Differences in Pharmacogenetics................................................ 83
Role of Pharmacogenetics in Drug Safety............................................... 84
Adverse Drug Reactions...................................................................... 84
ADRs in Children................................................................................ 84
Genetically Determined ADRs............................................................ 85
ADRs of Chemotherapy....................................................................... 86
Malignant Hyperthermia...................................................................... 87
Pharmacogenetics of Clozapine-Induced Agranulocytosis................. 87
Role of Pharmacogenetics in Warfarin Therapy.................................. 88
Role of Pharmacogenetics in Carbamazepine Therapy....................... 89
Role of Pharmacogenetics in Statin Therapy....................................... 89
FDA Consortium for Genetic Biomarkers of Serious
Adverse Events................................................................................ 90
Therapeutic Drug Monitoring, Phenotyping, and Genotyping................ 91
Therapeutic Drug Monitoring.............................................................. 91
Phenotyping......................................................................................... 91
Genotyping........................................................................................... 93
Genotyping vs. Phenotyping................................................................ 93
Phenomics................................................................................................ 94
Limitations of Genotype-Phenotype Association Studies................... 95
Molecular Toxicology in Relation to Personalized Medicines................ 95
Toxicogenomics................................................................................... 95
Gene Expression Studies...................................................................... 96
Genomics and the Prediction of Xenobiotic Toxicity.......................... 97
Pharmacogenetics in Clinical Trials........................................................ 97
Clinical Implications of Pharmacogenetics................................................. 98
Application of CYP450 Genotyping in Clinical Practice.................... 98
Genotype-Based Drug Dose Adjustment............................................. 98
Contents xiii

Examples of use of Pharmacogenetics in Clinical Pharmacology........... 99

Linking Pharmacogenetics with Pharmacovigilance............................... 100
Genetic Susceptibility to ADRs........................................................... 100
Linking Genetic Testing to Postmarketing ADR Surveillance............ 100
Recommendations for the Clinical Use of Pharmacogenetics................. 101
Limitations of Pharmacogenetics................................................................. 101
Future Role of Pharmacogenetics in Personalized Medicine...................... 102
Summary...................................................................................................... 102

5 Pharmacogenomics.................................................................................... 105
Introduction.................................................................................................. 105
Basics of Pharmacogenomics...................................................................... 105
Pharmacogenomics and Drug Discovery..................................................... 107
Preclinical Prediction of Drug Efficacy................................................... 108
Pharmacogenomics and Clinical Trials........................................................ 109
Impact of Genetic Profiling on Clinical Studies...................................... 109
Limitations of the Pharmacogenomic-Based Clinical Trials................... 111
Pharmacogenomic Aspects of Major Therapeutic Areas............................. 112
Oncogenomics.......................................................................................... 112
Oncogenes............................................................................................ 112
Tumor Suppressor Genes..................................................................... 113
Cardiogenomics....................................................................................... 113
Neurogenomics........................................................................................ 117
Pharmacogenomics of AD....................................................................... 117
Pharmacogenomics of Depression........................................................... 118
Pharmacogenomics of Schizophrenia...................................................... 118
Summary...................................................................................................... 119

6 Role of Pharmacoproteomics.................................................................... 121

Basics of Proteomics.................................................................................... 121
Proteomic Approaches to the Study of Pathophysiology of Diseases......... 122
Single Cell Proteomics for Personalized Medicine................................. 122
Diseases Due to Misfolding of Proteins................................................... 123
Therapies for Protein Misfolding......................................................... 123
Significance of Mitochondrial Proteome in Human Disease................... 124
Proteomic Technologies for Drug Discovery and Development................. 125
Role of Reverse-Phase Protein Microarray in Drug Discovery............... 125
Role of Proteomics in Clinical Drug Safety............................................ 125
Toxicoproteomics..................................................................................... 126
Application of Pharmacoproteomics in Personalized Medicine.................. 128
Summary...................................................................................................... 128

7 Role of Metabolomics in Personalized Medicine..................................... 129

Metabolomics and Metabonomics............................................................... 129
Metabolomics Bridges the Gap Between Genotype and Phenotype........... 130
xiv Contents

Metabolomics, Biomarkers and Personalized Medicine.............................. 131

Metabolomic Technologies.......................................................................... 131
Urinary Profiling by Capillary Electrophoresis....................................... 132
Lipid Profiling.......................................................................................... 133
Role of Metabolomics in Biomarker Identification
and Pattern Recognition....................................................................... 133
Validation of Biomarkers in Large-Scale Human Metabolomics
Studies.................................................................................................. 134
Pharmacometabonomics.............................................................................. 134
Metabonomic Technologies for Toxicology Studies................................... 135
Metabonomics/Metabolomics and Personalized Nutrition.......................... 136
Summary...................................................................................................... 136

8 Personalized Biological Therapies............................................................ 137

Introduction.................................................................................................. 137
Recombinant Human Proteins..................................................................... 137
Therapeutic Monoclonal Antibodies............................................................ 138
Cell Therapy................................................................................................. 138
Autologous Tissue and Cell Transplants.................................................. 139
Stem Cells................................................................................................ 139
Role of Stem Cells Derived from Unfertilized Embryos..................... 139
Cloning and Personalized Cell Therapy.................................................. 140
Use of Stem Cells for Drug Testing......................................................... 140
Gene Therapy............................................................................................... 140
Personalized Vaccines.................................................................................. 141
Personalized Vaccines for Viral Diseases................................................ 141
Personalized Cancer Vaccines.................................................................. 142
Patient-Specific Cancer Vaccines......................................................... 142
Antigen-Specific Vaccines................................................................... 143
Autologous Cell Vaccines.................................................................... 143
Personalized Melanoma Vaccines........................................................ 145
Antisense Therapy....................................................................................... 145
RNA Interference..................................................................................... 146
MicroRNAs.............................................................................................. 146
Summary...................................................................................................... 147

9 Development of Personalized Medicine................................................... 149

Introduction.................................................................................................. 149
Non-genomic Factors in the Development of Personalized Medicine......... 150
Personalized Medicine Based on Circadian Rhythms............................. 150
Intestinal Microflora................................................................................ 151
Gut Microbiome Compared to Human Genome.................................. 151
Metabolic Interactions of the Host and the Intestinal Microflora........ 152
Role of Drug Delivery in Personalized Medicine.................................... 152
Role of Molecular Imaging in Personalized Medicine............................ 153
Contents xv

Personalized Approach to Clinical Trials.............................................. 153

Use of Bayesian Approach in Clinical Trials..................................... 153
Individualizing Risks and Benefits in Clinical Trials........................ 154
Clinical Trials of Therapeutics and Companion Diagnostics............ 155
Role of Genetic Banking Systems and Databases..................................... 155
Role of Biobanks in the Development of Personalized Medicine......... 155
UK Biobank........................................................................................... 156
Biobanking and Development of Personalized
Medicine in the EU............................................................................ 156
CARTaGENE for Biobanks in Canada.................................................. 157
Personalized Medicine Based on PhysioGenomics™ Technology....... 158
Role of Bioinformatics in Development of Personalized Medicine.......... 159
Health Information Management........................................................... 160
Electronic Health Records................................................................. 160
Linking Patient Medical Records and Genetic Information.............. 161
Management of Personal Genomic Data........................................... 162
Personalized Prognosis of Disease......................................................... 162
Integration of Technologies for Development
of Personalized Medicine................................................................... 163
Summary.................................................................................................... 163

10 Personalized Therapy for Cancer........................................................... 165

Introduction................................................................................................ 165
Challenges of Cancer Classification...................................................... 165
Relationships of Technologies for Personalized
Management of Cancer...................................................................... 166
Impact of Molecular Diagnostics on the Management of Cancer............. 167
Analysis of RNA Splicing Events in Cancer......................................... 167
Analysis of Chromosomal Alterations in Cancer Cells......................... 168
Cancer Classification Using Microarrays.............................................. 168
Detection of Loss of Heterozygosity (LOH)......................................... 169
Diagnosis of Cancer of an Unknown Primary....................................... 170
Diagnostics for Detection of Minimal Residual Disease (MRD).......... 170
Fluorescent In Situ Hybridization.......................................................... 171
Gene Expression Profiling..................................................................... 171
Gene Expression Profiles Predict Chromosomal
Instability in Tumors.............................................................................. 172
Isolation and Characterization of Circulating Tumor Cells (CTCs)...... 173
Modulation of CYP450 Activity for Cancer Therapy........................... 173
Personalized Therapies Based on Oncogenic Pathway Signatures........ 174
Role of Molecular Imaging in Personalized Therapy of Cancer........... 175
Molecular Imaging for Personalized Drug
Development in Oncology................................................................. 175
Molecular Imaging as Guide to Cancer Treatment............................ 176
Functional Diffusion MRI.................................................................. 177
xvi Contents

Role of FDG-PET/CT in Personalizing Cancer Treatment............... 178

Tumor Imaging and Elimination by Targeted Gallium Corrole......... 179
Unraveling the Genetic Code of Cancer................................................ 179
Cancer Prognosis....................................................................................... 180
Detection of Mutations for Risk Assessment and Prevention................ 181
Impact of Biomarkers on Management of Cancer..................................... 181
Predictive Biomarkers for Cancer.......................................................... 181
HER-2/neu Oncogene as a Biomarker for Cancer................................. 182
l-asparaginase (l-ASP)Treatment of Cancer Guided
by a Biomarker................................................................................... 182
Determination of Response to Therapy..................................................... 183
Phenotype-Based Cell Culture Assays................................................... 183
Ex Vivo Testing of Tumor Biopsy for Chemotherapy Sensitivity......... 183
Genomic Approaches to Predict Response to Anticancer Agents......... 184
Gene Expression Patterns to Predict Response
of Cancer to Therapy..................................................................... 184
Genomic Analysis of Tumor Biopsies............................................... 184
Mutation Detection at Molecular Level............................................. 185
Role of Genetic Variations in Susceptibility
to Anticancer Drugs....................................................................... 185
Proteomic Analysis of Tumor Biopsies to Predict Response
to Treatment....................................................................................... 185
Real-time Apoptosis Monitoring........................................................... 186
Serum Nucleosomes as Indicators of Sensitivity to Chemotherapy...... 186
Targeted Microbubbles to Tumors for Monitoring
Anticancer Therapy............................................................................ 187
Tissue Systems Biology Approach to Personalized
Management of Cancer...................................................................... 188
Targeted Cancer Therapies......................................................................... 188
Targeting Glycoproteins on Cell Surface............................................... 188
Targeting Pathways in Cancer................................................................ 189
Functional Antibody-Based Personalized Therapies................................. 189
Personalized Radiation Therapy................................................................ 190
Molecular Diagnostics Combined with Cancer Therapeutics................... 191
Aptamers for Combined Diagnosis and Therapeutics of Cancer........... 192
Role of Nanobiotechnology in Personalized Management of Cancer....... 192
Design of Future Cancer Therapies........................................................... 193
Screening for Personalized Anticancer Drugs....................................... 194
Role of Epigenetics in Development of Personalized
Cancer Therapies............................................................................... 194
Personalized Therapy of Cancer Based on Cancer Stem Cells.............. 195
Role of Oncoproteomics in Personalized Therapy of Cancer.................... 195
Cancer Tissue Proteomics...................................................................... 196
Pharmacogenomic-Based Chemotherapy.................................................. 197
Whole Genome Technology to Predict Drug Resistance....................... 197
Contents xvii

Anticancer Drug Selection Based on Molecular Characteristics

of Tumor............................................................................................ 197
Testing Microsatellite-Instability for Response to Chemotherapy........ 198
Pharmacogenetics of Cancer Chemotherapy............................................. 199
CYP1A2................................................................................................. 199
Thiopurine Methyltransferase................................................................ 200
Dihydropyrimidine Dehydrogenase....................................................... 201
UGT1A1 Test as Guide to Irinotecan Therapy...................................... 201
Role of Computational Models in Personalized Anticancer Therapy....... 202
A Computational Model of Kinetically Tailored Treatment.................. 202
Mathematical Modeling of Tumor Microenvironments......................... 202
Molecular Profiling of Cancer................................................................... 203
Drug Resistance in Cancer......................................................................... 204
Detection of Drug Resistance in Cancer by Metabolic Profiling.......... 205
Determination of Chemotherapy Response
by Topoisomerase Levels................................................................... 205
A Systems Biology Approach to Drug Resistance in CRC................... 206
Management of Drug Resistance in Leukemia...................................... 206
Overexpression of Multidrug Resistance Gene..................................... 207
P53 Mutations........................................................................................ 207
A Chemogenomic Approach to Drug Resistance.................................. 208
Examples of Personalized Management of Cancer................................... 208
Personalized Management of Breast Cancer......................................... 208
Genetic Testing in Breast Cancer as a Guide to Treatment............... 209
Pharmacogenetics of Breast Cancer................................................... 210
Molecular Diagnostics in Breast Cancer............................................ 210
Racial Factors in the Management of Breast Cancer......................... 212
Proteomics-Based Personalized Management of Breast Cancer....... 212
Tests for Prognosis of Breast Cancer................................................. 213
Developing Personalized Drugs for Breast Cancer............................ 215
Developing Personalized Drugs for Triple-Negative
Breast Cancer..................................................................................... 216
Predicting Response to Chemotherapy in Breast Cancer.................. 216
Prediction of Resistance to Therapy in Breast Cancer....................... 219
Prediction of Adverse Reaction to RT in Breast Cancer.................... 220
Prediction of Recurrence in Breast Cancer for
Personalizing Therapy................................................................... 220
TAILORx (Trial Assigning Individualized Options
for Treatment)................................................................................ 222
Gene Expression Plus Conventional Predictors
of Breast Cancer............................................................................. 223
Future Development of Gene Expression Microarrays
for Breast Cancer........................................................................... 224
Personalized Management of Ovarian Cancer....................................... 224
Personalized Management of Hematological Malignancies.................. 227
xviii Contents

Personalized Management of Acute Leukemias................................ 227

Personalized Management of Chronic Lymphocytic Leukemia........ 229
Personalized Management of Multiple Myeloma (MM)................... 229
Personalized Management B Cell Lymphomas................................. 231
Personalized Vaccine for Follicular Lymphoma................................ 231
Personalized Management of Myelodysplasia................................... 232
Personalized Management of Malignant Melanoma............................. 232
Personalized Management of Gastrointestinal Cancer.......................... 232
Personalized Management of Esophageal Cancer............................. 232
Personalized Management of CRC.................................................... 233
Personalized Management of Lung Cancer........................................... 236
Determination of Outcome of EGFR Tyrosine Kinase
Inhibitor Treatment........................................................................ 236
Testing for Response to Chemotherapy in Lung Cancer................... 239
Testing for Prognosis of NSCLC....................................................... 239
Testing for Recurrence of Lung Cancer............................................. 240
Role of a New Classification System in the Management
of Lung Cancer.............................................................................. 240
Personlized Management of Prostate Cancer........................................ 241
Benefit of Lifestyle Changes Shown by Gene
Expression Studies......................................................................... 241
Personalized Management of Brain Cancer........................................... 242
Genetics and Genomics of Brain Cancer........................................... 242
Molecular Diagnostics for Personalized Management
of Brain Cancer.............................................................................. 244
Personalized Chemotherapy of Brain Tumors................................... 246
Biosimulation Approach to Personalizing Treatment
of Brain Cancer.............................................................................. 247
Personalized Therapy of Oligodendroglial Tumors........................... 248
Personalized Therapy of Neuroblastomas......................................... 249
Personalized Management of Germ Cell Brain Tumors.................... 250
Future of Cancer Therapy.......................................................................... 250
Challenges for Developing Personalized Cancer Therapies.................. 250
The Cancer Genome Atlas..................................................................... 251
Role of the International Cancer Genome Consortium.......................... 251
Using Computer and Imaging Technologies
to Personalize Cancer Treatment....................................................... 253
Integrated Genome-Wide Analysis of Cancer for
Personalized Therapy......................................................................... 253
Summary.................................................................................................... 254

11 Personalized Management of Neurological Disorders.......................... 255

Introduction................................................................................................ 255
Personalized Drug Development for Neurological Disorders................... 255
Personalized Drug Discovery................................................................. 255
Contents xix

Molecular Imaging and CNS Drug Development.................................. 255

Personalized Management of AD.............................................................. 257
Personalized Management of PD............................................................... 258
Discovery of Subgroup-Selective Drug Targets in PD.......................... 259
Personalized Management of Epilepsy...................................................... 259
Choice of the Right AED....................................................................... 260
Pharmacogenetics of Epilepsy........................................................... 260
Pharmacogenomics of Epilepsy............................................................. 261
Drug Resistance in Epilepsy.................................................................. 262
Future Prospects for Epilepsy................................................................ 263
Personalized Management of Migraine..................................................... 264
Personalized Treatment of MS................................................................... 264
MBP8298............................................................................................... 265
Pharmacogenomics of IFN-b Therapy in MS.................................... 266
Future Prospects of Personalized Therapy of MS.............................. 267
Personalized Management of Psychiatric Disorders.................................. 267
Psychopharmacogenetics....................................................................... 267
COMT Genotype and Response to Amphetamine............................. 268
Genotype and Response to Methylphenidate in
Children with ADHD..................................................................... 268
Personalized Antipsychotic Therapy..................................................... 269
Personalized Antidepressant Therapy.................................................... 272
Pretreatment EEG to Predict Adverse Effects to Antidepressants..... 273
Individualization of SSRI Treatment................................................. 273
Vilazodone with a Test for Personalized Treatment
of Depression................................................................................. 275
Summary.................................................................................................... 275

12 Personalized Therapy of Cardiovascular Diseases............................... 277

Introduction................................................................................................ 277
Role of Cardiovascular Diagnostics in Personalized Management........... 277
Testing in Coronary Heart Disease........................................................ 277
SNP Genotyping in Cardiovascular Disorders....................................... 278
Cardiovascular Disorders with a Genetic Component........................... 279
Gene Variant as a Risk Factor for Sudden Cardiac Death................. 281
SNP Chip for Study of Cardiovascular Diseases............................... 282
Pharmacogenomics of Cardiovascular Disorders.................................. 282
Modifying the Genetic Risk for MI....................................................... 283
Management of Heart Failure................................................................ 283
b-Blockers.......................................................................................... 283
Bucindolol.......................................................................................... 284
BiDil................................................................................................... 284
Management of Hypertension................................................................ 285
Pharmacogenomics of Diuretic Drugs............................................... 286
Pharmacogenomics of ACE Inhibitors.............................................. 287
xx Contents

Management of Hypertension by Personalized Approach................. 287

Pharmacogenetics of Lipid-Lowering Therapies................................... 288
Polymorphisms in Genes Involved in Cholesterol Metabolism......... 288
Role of eNOS Gene Polymorphisms................................................. 289
The STRENGTH Study..................................................................... 290
Personalized Management of Women with Hyperlipidemia............. 291
Thrombotic Disorders............................................................................ 291
Factor V Leiden Mutation.................................................................. 291
Anticoagulant Therapy....................................................................... 292
Nanotechnology-Based Personalized Therapy of
Cardiovascular Diseases.................................................................... 293
Project euHeart for Personalized Management of
Cardiovascular Diseases.................................................................... 294
Concluding Remarks.............................................................................. 294
Summary.................................................................................................... 295

13 Personalized Management of Miscellaneous Disorders....................... 297

Management of Viral Infections................................................................ 297
Management of HIV.............................................................................. 297
Genetics of Human Susceptibility to HIV Infection.......................... 297
Pharmacogenomics of Antiretroviral Agents..................................... 298
Role of Diagnostic Testing in HIV.................................................... 299
CD4 Counts as a Guide to Drug Therapy for AIDS.......................... 299
Drug-Resistance in HIV..................................................................... 299
Measurement of Replication Capacity............................................... 300
Prevention of Adverse Reactions to Antiviral Drugs......................... 300
Role of Genetic Variations in Susceptibility to HIV-1....................... 301
Pharmacogenetics and HIV Drug Safety........................................... 302
Treatment of Hepatitis B........................................................................ 302
Treatment of Hepatitis C........................................................................ 302
Personalized Management of Tuberculosis (TB)....................................... 304
Personalized Management of Skin Disorders............................................ 305
Personalized Therapy of Rheumatoid Arthritis (RA)................................ 305
DIATSTATTM Anti-Cyclic Citrullinated Peptides in RA........................ 307
Personalization of COX-2 Inhibitor Therapy......................................... 307
Personalization of Infliximab Therapy.................................................. 308
Personalized Therapy of Asthma............................................................... 308
Genetic Polymorphism and Response to b2-Adrenergic Agonists........ 308
Genotyping in Asthma........................................................................... 309
Personalized Approaches in Immunology................................................. 310
Pharmacogenetics and Pharmacogenomics of
Immunosuppressive Agents............................................................... 311
Personalized Immunosuppressant Therapy in Organ Transplants......... 311
Personalized Management of Pain............................................................. 312
Pharmacogenetics/Pharmacogenomics of Pain...................................... 313