Abstract
Summary
The aim of personalized medicine or individualized treatment is to match the
right drug to the right patient and, in some cases, even to design the
appropriate treatment for a patient according to his/her genotype. This report
describes the latest concepts of development of personalized medicine based on
pharmacogenomics, pharmacogenetics,pharmacoproteomics, and metabolomics. Basic
technologies of molecular diagnostics play an important role, particularly
those for single nucleotide polymorphism (SNP) genotyping. Diagnosis is
integrated with therapy for selection of the treatment as well for monitoring
the results. Biochip/microarray technologies are also important and finally
bioinformatics is needed to analyze the immense amount of data generated by
various technologies.
Pharmacogenetics, the study of influence of genetic factors on drug action and
metabolism, is used for predicting adverse reactions of drugs. Several enzymes
are involved in drug metabolism of which the most important ones are those
belonging to the family of cytochrome P450. The knowledge of the effects of
polymorphisms of genes for the enzymes is applied in drug discovery and
development as well as in clinical use of drugs. Cost-effective methods for
genotyping are being developed and it would be desirable to include this
information in the patient's record for the guidance of the physician to
individualize the treatment. Pharmacogenomics, a term that overlaps with
pharmacogenetics but is distinct, deals with the application of genomics to
drug discovery and development. It involves the mechanism of action of drugs
on cells as revealed by gene expression patterns. Pharmacoproteomics is an
important contribution to personalized medicine as it is a more functional
representation of patient-to-patient variation than that provided by
genotyping.A 'pharmacometabonomic' approach to personalizing drug treatment is
also described.
Biological therapies such as those which use patient's own cells are
considered to be personalized medicines. Vaccines are prepared from individual
patient's tumor cells. Individualized therapeutic strategies using monoclonal
bodies can be directed at specific genetic and immunologic targets. Ex vivo
gene therapy involves the genetic modification of the patient's cells in
vitro, prior to reimplantation of these cells in the patient's body.
Various technologies are integrated to develop personalized therapies for
specific therapeutic areas described in the report. Examples of this are
genotyping for drug resistance in HIV infection, personalized therapy of
cancer, antipsychotics for schizophrenia, antidepressant therapy,
antihypertensive therapy and personalized approach to neurological disorders.
Although genotyping is not yet a part of clinically accepted routine, it is
expected to have this status by the year 2016.
Several players are involved in the development of personalized therapy.
Pharmaceutical and biotechnology companies have taken a leading role in this
venture in keeping with their future role as healthcare enterprises rather
than mere developers of technologies and manufacturers of medicines.
Ethical issues are involved in the development of personalized medicine mainly
in the area of genetic testing. These along with social issues and
consideration of race in the development of personalized medicine are
discussed. Regulatory issues are discussed mainly with reference to the FDA
guidelines on pharmacogenomics.
Increase in efficacy and safety of treatment by individualizing it has
benefits in financial terms. Information is presented to show that
personalized medicine will be cost-effective in healthcare systems. For the
pharmaceutical companies, segmentation of the market may not leave room for
conventional blockbusters but smaller and exclusive markets for personalized
medicines would be profitable. Marketing opportunities for such a system are
described with market estimates from 2011-2021.
Profiles of 255 companies involved in developing technologies for personalized
medicines, along with 475 collaborations are included in the part II of the
report. Finally the bibliography contains over 630 selected publications cited
in the report.The report is supplemented by 64 tables and 18 figures.
Table of Contents
Part I
0. Executive Summary 20
1. Basic Aspects 22
- Definition of personalized medicine 22
- History of medical concepts relevant to personalized medicine 23
- Molecular biological basis of personalized medicine 25
- The human genome 25
- Chromosomes 26
- Genes 26
- The genetic code 26
- Gene expression 27
- DNA sequences and structure 27
- Genetic variations in the human genome 27
- Single nucleotide polymorphisms 28
- Copy number variations in the human genome 28
- Insertions and deletions in the human genome 30
- Large scale variation in human genome 31
- Structural variations in the human genome 31
- Mapping and sequencing of structural variation from human genomes 31
- 1000 Genomes Project 32
- Role of DNA sequencing in the development of personalized medicine 34
- Human Variome Project 34
- Interconnected genetic and genomic patterns in human diseases 34
- Basics technologies for developing personalized medicine 35
- Definitions of technologies relevant to personalized medicine 35
- Problems with the ICH definitions of pharmacogenomcis and pharmacogenetics
36
- Relationship of various technologies to personalized medicine 36
- Conventional medicine versus personalized medicine 37
- Role of genetics in future approaches to healthcare 37
- Genetic medicine 37
- Human disease and genes 37
- Genetic and environmental interactions in etiology of human diseases 38
- Role of genetics in development of personalized medicines 38
- Genetic databases 39
- Genetic epidemiology 39
- Limitations of medical genetics and future prospects 39
- Genetics vs. epigenetics 40
- Role of systems biology in personalized medicine 40
- Systems pharmacology 41
- Systems medicine 42
- Synthetic biology and development of personalized medicines 43
- A personalized approach to environmental factors in disease 43
- Reclassification of diseases 44
2. Molecular Diagnostics in Personalized Medicine 46
- Introduction 46
- Molecular diagnostic technologies 46
- PCR-based methods 47
- DirectLinear"! Analysis 47
- Denaturing high-performance liquid chromatography 48
- Multiplex Allele-Specific Diagnostic Assay 48
- Representational oligonucleotide microarray analysis 48
- Restriction fragment length polymorphism (RFLP) 48
- Real-time PCR for detection of CNVs 48
- Non-PCR methods 49
- Arrayed primer extension (APEX) 49
- Enzymatic Mutation Detection (EMD) 49
- DNA sequencing 49
- Sanger-sequencing technology 50
- ABI PRISMR 310 Genetic Analyzer 51
- High-throughput paired end transcriptome sequencing 51
- Emerging sequencing technologies 51
- 4300 DNA analyzer 52
- Apollo 100 52
- "Color blind" approach to DNA sequencing 53
- Cyclic array sequencing 53
- CEQ"! 8000 53
- DeepCAGE sequencing 53
- Electron microscope-based DNA sequencing 54
- Genometrica™ sequencer 54
- GS-FLEX system (Roche/454) 55
- IBS sequencing technology 56
- Illumina Genome Analyzer System 56
- MegaBACE 500 57
- Microdroplet-based PCR for large-scale targeted sequencing 57
- Multiplex amplification of human DNA sequences 58
- Nanoscale sequencing 58
- Polonator sequencer 58
- RainStorm"! microdroplet technology 59
- Sequential DEXAS 59
- SOLiD technology 60
- Sequencing by hybridization 61
- Whole genome sequencing 61
- Bioinformatic tools for analysis of genomic sequencing data 61
- Detection of single molecules in real time 62
- Direct observation of nucleotide incorporation 62
- Molecular Combing 62
- Nanopore sequencing 62
- DNA sequence by use of nanoparticles 63
- Zero-mode waveguide nanostructure arrays 63
- Future prospects of sequencing 63
- Role of sequencing in development of personalized medicine 64
- Biochips and microarrays 65
- Application of biochip technology in developing personalized medicine 65
- Standardizing the microarrays 66
- Biochip technologies 66
- GeneChip 67
- AmpliChip CYP450 67
- Microfluidics 68
- Lab-on-a-chip 69
- Micronics' microfluidic technology 69
- LabCD 69
- Microfluidic automated DNA analysis using PCR 70
- Integrated microfluidic bioassay chip 70
- Electronic detection of nucleic acids on microarrays 70
- Strand displacement amplification on a biochip 71
- Rolling circle amplification on DNA microarrays 71
- Universal DNA microarray combining PCR and ligase detection reaction 71
- Protein biochips 72
- ProteinChip 72
- LabChip for protein analysis 73
- TRINECTIN proteome chip 73
- Protein expression microarrays 74
- Microfluidic devices for proteomics-based diagnostics 74
- New developments in protein biochips/microarrays 74
- Protein biochips/microarrays for personalized medicine 75
- SNP genotyping 75
- Genotyping and haplotyping 76
- Haplotype Specific Extraction 77
- Computation of haplotypes 77
- HapMap project 78
- Haplotyping for whole genome sequencing 79
- Predictingdrug response with HapMap 79
- Companies developing haplotyping technology 79
- Technologies for SNP analysis 80
- Biochip and microarray-based detection of SNPs 81
- SNP genotyping by MassARRAY 81
- Biochip combining BeadArray and ZipCode technologies 81
- SNP-IT primer-extension technology 82
- Affymetrix Variation Detection Arrays 82
- Use of NanoChip for detection of SNPs 82
- Electrochemical DNA probes 83
- Single base extension-tag array 83
- Laboratory Multiple Analyte Profile 83
- PCR-CTPP (confronting two-pair primers) 84
- SNP genotyping on a genome-wide amplified DOP-PCR template 84
- TaqMan real-time PCR 84
- Non-Enzymatic Amplification Technology 84
- SNP genotyping with gold nanoparticle probes 85
- Locked nucleic acid 85
- Molecular inversion probe based assays 85
- Pyrosequencing 86
- Reversed enzyme activity DNA interrogation test 86
- Smart amplification process version 2 87
- Zinc finger proteins 87
- UCAN method (Takara Biomedical) 87
- Mitochondrial SNPs 88
- Limitations of SNP in genetic testing 88
- Concluding remarks on SNP genotyping 88
- Companies involved in developing technologies/products for SNP analysis
89
- Impact of SNPs on personalized medicine 90
- Detection of copy number variations 91
- Study of rare variants in pinpointing disease-causing genes 91
- Optical Mapping 92
- Role of nanobiotechnology in molecular diagnostics 92
- Cantilevers for personalized medical diagnostics 93
- Nanopore-based technology for single molecule identification 93
- Role of biomarkers in personalized medicine 94
- Biomarkers for diagnostics 94
- Biomarkers for drug development 95
- Application of proteomics in molecular diagnosis 95
- Proteomic strategies for biomarker identification 95
- Proteomic technologies for detection of biomarkers in body fluids 95
- Protein patterns 96
- Layered Gene Scanning 96
- Comparison of proteomic and genomic approaches in personalized medicine
97
- Gene expression profiling 97
- DNA microarrays 98
- Analysis of single-cell gene expression 98
- Gene expression profiling based on alternative RNA splicing 99
- Whole genome expression array 100
- Tangerine"! expression profiling 100
- Gene expression analysis on biopsy samples 101
- Profiling gene expression patterns of white blood cells 101
- Serial analysis of gene expression (SAGE) 102
- Multiplexed Molecular Profiling 102
- Gene expression analysis using competitive PCR and MALDI TOF MS 103
- Monitoring in vivo gene expression by magnetic resonance imaging 103
- Companies involved in gene expression analysis 103
- Monitoring in vivo gene expression by molecular imaging 104
- Molecular imaging and personalized medicine 105
- Glycomics-based diagnostics 105
- Combination of diagnostics and therapeutics 105
- Use of molecular diagnostics for stratification in clinical trials 106
- Companion diagnostics 106
- Companies involved in companion diagnostics 106
- Point-of-care diagnosis 108
- Companies developing point-of-care diagnostic technologies 109
- Point-of-care diagnosis of infections 111
- Advantages versus disadvantages of point-of-care diagnosis 112
- Future prospects of point-of-care diagnosis 112
- Genetic testing for disease predisposition 113
- Preventive genetics by early diagnosis of mitochondrial diseases 113
- Direct-to-consumer genetic services 113
- Role of diagnostics in integrated healthcare 115
- Concept of integrated healthcare 115
- Components of integrated healthcare 116
- Screening 116
- Disease prediction 116
- Early diagnosis 116
- Prevention 116
- Therapy based on molecular diagnosis 116
- Monitoring of therapy 116
- Advantages and limitations of integrated healthcare 117
- Commercially available systems for integrated healthcare 117
- Future of molecular diagnostics in personalized medicine 118
3. Pharmacogenetics 120
- Basics of pharmacogenetics 120
- Role of molecular diagnostics in pharmacogenetics 121
- Role of pharmacogenetics in pharmaceutical industry 122
- Study of the drug metabolism and pharmacological effects 122
- Causes of variations in drug metabolism 122
- Enzymes relevant to drug metabolism 123
- Pharmacogenetics of phase I metabolism 123
- CYP450 123
- P450 CYP 2D6 inhibition by selective serotonin reuptake inhibitors 125
- Cytochrome P450 polymorphisms and response to clopidogrel 126
- Lansoprazole and cytochrome P450 126
- Glucose-6-phosphate dehydrogenase 126
- Pharmacogenetics of phase II metabolism 127
- N-Acetyltransferase 127
- Uridine diphosphate-glucuronosyltransferase 128
- Measurement of CYP isoforms 128
- Polymorphism of drug transporters 129
- Genetic variation in drug targets 129
- Polymorphisms of kinase genes 130
- Effect of genetic polymorphisms on disease response to drugs 130
- Ethnic differences in drug metabolism 131
- Gender differences in pharmacogenetics 131
- Role of pharmacogenetics in drug safety 132
- Adverse drug reactions 132
- Adverse drug reactions in children 133
- Adverse drug reactions related to toxicity of chemotherapy 133
- Genetically determined adverse drug reactions 133
- Malignant hyperthermia 135
- Pharmacogenetics of clozapine-induced agranulocytosis 135
- Role of pharmacogenetics in warfarin therapy 135
- Role of pharmacogenetics in antiplatelet therapy 136
- Role of pharmacogenetics in carbamazepine therapy 138
- Role of pharmacogenetics in statin therapy 138
- FDA consortium linking genetic biomarkers to serious adverse events 139
- Therapeutic drug monitoring, phenotyping, and genotyping 139
- Therapeutic drug monitoring 140
- Phenotyping 140
- Genotyping 141
- Genotyping vs phenotyping 141
- Phenomics 142
- Limitations of genotype-phenotype association studies 143
- Molecular toxicology in relation to personalized medicines 143
- Toxicogenomics 143
- Biomarkers of drug toxicity 143
- Drug-induced mitochondrial toxicity 144
- Companies involved in molecular toxicology 144
- Gene expression studies 145
- Pharmacogenetics in clinical trials 145
- Postmarketing pharmacogenetics 146
- Clinical implications of pharmacogenetics 146
- Application of CYP450 genotyping in clinical practice 146
- Pharmacogenomic biomarker information in drug labels 146
- Genotype-based drug dose adjustment 147
- Examples of use of pharmacogenetics in clinical pharmacology 147
- Genotyping for identifying responders to sulfasalazine 147
- HLA alleles associated with lumiracoxib-related liver injury 147
- Pharmacogenetic basis of thiopurine toxicity 148
- Tranilast-induced hyperbilirubinemia due to gene polymorphism 148
- Linking pharmacogenetics with pharmacovigilance 148
- Genetic susceptibility to ADRs 148
- Linking genetic testing to postmarketing ADR surveillance 149
- Recommendations for the clinical use of pharmacogenetics 149
- Limitations of pharmacogenetics 150
- Pharmacoepigenomics vs pharmacogenetics in drug safety 150
- Future role of pharmacogenetics in personalized medicine 151
4. Pharmacogenomics 152
- Introduction 152
- Basics of pharmacogenomics 153
- Pharmacogenomics and drug discovery 153
- Preclinical prediction of drug efficacy 155
- Pharmacogenomics and clinical trials 155
- Impact of genetic profiling on clinical studies 156
- Limitations of the pharmacogenomic-based clinical trials 157
- Pharmacogenomic aspects of major therapeutic areas 158
- Oncogenomics 158
- Oncogenes 158
- Tumor suppressor genes 159
- Cardiogenomics 160
- Neuropharmacogenomics 162
- Pharmacogenomics of Alzheimer's disease 162
- Pharmacogenomics of depression 163
- Pharmacogenomics of schizophrenia 163
- Companies involved in neurogenomics-based drug discovery 164
5. Role of Pharmacoproteomics 166
- Basics of proteomics 166
- Proteomic approaches to the study of pathophysiology of diseases 166
- Single cell proteomics for personalized medicine 167
- Diseases due to misfolding of proteins 167
- Therapies for protein misfolding 168
- Significance of mitochondrial proteome in human disease 169
- Proteomic technologies for drug discovery and development 169
- Role of reverse-phase protein microarray in drug discovery 169
- Role of proteomics in clinical drug safety 169
- Toxicoproteomics 170
- Application of pharmacoproteomics in personalized medicine 171
6. Role of Metabolomics in Personalized Medicine 172
- Metabolomics and metabonomics 172
- Metabolomics bridges the gap between genotype and phenotype 172
- Metabolomics, biomarkers and personalized medicine 173
- Metabolomic technologies 173
- Urinary profiling by capillary electrophoresis 174
- Lipid profiling 174
- Role of metabolomics in biomarker identification and pattern recognition
175
- Validation of biomarkers in large-scale human metabolomics studies 175
- Pharmacometabonomics 175
- Metabonomic technologies for toxicology studies 176
- Metabonomics/metabolomics and personalized nutrition 176
7. Personalized Biological Therapies 178
- Introduction 178
- Recombinant human proteins 178
- Therapeutic monoclonal antibodies 178
- Cell therapy 179
- Autologous tissue and cell transplants 179
- Stem cells 179
- Role of stem cells derived from unfertilized embryos 179
- Cloning and personalized cell therapy 180
- Use of stem cells for drug testing 180
- Gene therapy 180
- Personalized vaccines 181
- Personalized vaccines for viral diseases 181
- Personalized cancer vaccines 181
- Antisense therapy 181
- RNA interference 182
- MicroRNAs 183
8. Personalized Medicine in Major Therapeutic Areas 184
- Introduction 184
- Management of infections 185
- Management of HIV 185
- CD4 counts as a guide to drug therapy for AIDS 185
- Drug-resistance in HIV 185
- Genetics of human susceptibility to HIV infection 186
- Measurement of Replication Capacity 187
- Personalized vaccine for HIV 187
- Prevention of adverse reactions to antiviral drugs 187
- Pharmacogenetics and HIV drug safety 188
- Pharmacogenomics of antiretroviral agents 188
- Role of diagnostic testing in management of HIV 189
- Role of genetic variations in susceptibility to HIV-1 189
- Personalized treatment of hepatitis B 189
- Personalized treatment of hepatitis C 190
- Responders vs non-responders to treatment for hepatitis C 190
- Drug resistance in hepatitis C 191
- Personalized management of tuberculosis 191
- Personalized management of fungal infections 192
- Psychiatric disorders 192
- Psychopharmacogenetics/psychopharmacodynamics 193
- Serotonin genes 193
- Calcium channel gene 193
- Dopamine receptor genes 194
- COMT genotype and response to amphetamine 194
- Methylenetetrahydrofolate reductase 194
- Genotype and response to methylphenidate in children with ADHD 194
- Personalized antipsychotic therapy 195
- Personalized antidepressant therapy 197
- EEG to predict adverse effects and evaluate antidepressant efficacy 198
- Individualization of SSRI treatment 198
- Treatment resistant depression 199
- Vilazodone with a test for personalized treatment of depression 199
- Neurological disorders 200
- Personalized management of Alzheimer's disease 200
- Personalized management of Parkinson's disease 201
- Discovery of subgroup-selective drug targets in PD 202
- Personalized management of Epilepsy 202
- Choice of the right AED 203
- Pharmacogenetics of epilepsy 203
- Pharmacogenomics of epilepsy 203
- Drug resistance in epilepsy 204
- Future prospects for management of epilepsy 205
- Personalized management of migraine 206
- Individualization of use of triptans for migraine 206
- Multitarget therapeutics for personalized treatment of headache 207
- Personalized management of stroke 207
- Brain imaging in trials of restorative therapies for stroke 207
- Decisions for evacuation of intracerebral hemorrhage 208
- Revascularization procedures in chronic post-stroke stage 208
- Personalized treatment of multiple sclerosis 208
- Immunopathological patterns of demyelination for assessing therapy 209
- Personalizing mitoxantrone therapy of multiple sclerosis 209
- Fusokine method of personalized cell therapy of multiple sclerosis 210
- MBP8298 210
- Pharmacogenomics of IFN-β therapy in multiple sclerosis 211
- T cell-based personalized vaccine for MS 212
- Cardiovascular disorders 212
- Role of diagnostics in personalized management of cardiovascular disease
212
- Testing in coronary heart disease 212
- SNP genotyping in cardiovascular disorders 213
- Cardiovascular disorders with a genetic component 214
- Gene variant as a risk factor for sudden cardiac death 215
- KIF6 gene test as a guide to management of heart disease 216
- SNP Chip for study of cardiovascular diseases 216
- Pharmacogenomics of cardiovascular disorders 216
- Modifying the genetic risk for myocardial infarction 217
- Management of heart failure 217
- βblockers 217
- Bucindolol 218
- BiDil 218
- Management of hypertension 218
- Pharmacogenomics of diuretic drugs 219
- Pharmacogenomics of ACE inhibitors 219
- Management of hypertension by personalized approach 220
- Prediction of antihypertensive activity of rostafuroxin 221
- Pharmacogenetics of lipid-lowering therapies 221
- Polymorphisms in genes involved in cholesterol metabolism 221
- Role of eNOS gene polymorphisms 222
- The STRENGTH study 223
- Personalized management of women with hyperlipidemia 223
- Thrombotic disorders 224
- Factor V Leiden mutation 224
- Anticoagulant therapy 224
- Antiplatelet therapy 225
- Nanotechnology-based personalized therapy of cardiovascular diseases
225
- Project euHeart for personalized management of heart disease 226
- Concluding remarks 226
- Personalized management of pulmonary disorders 227
- Role of genetic ancestory in lung function 227
- Personalized therapy of asthma 227
- Biomarkers for predicting response to corticosteroid therapy 228
- Genetic polymorphism and response to β2-adrenergic agonists 228
- Genotyping in asthma 228
- IgE as guide to dosing of omalizumab for asthma 229
- Lebrikizumab for personalised treatment of asthma 229
- Personalized management of chronic obstructive pulmonary disease 230
- Personalized management of skin disorders 231
- Genetic testing for personalized skin care 231
- Management of hair loss based on genetic testing 231
- Personalized therapy of rheumatoid arthritis 231
- DIATSTAT"! anti-cyclic citrullinated peptides in rheumatoid arthritis
232
- Personalization of COX-2 inhibitor therapy 233
- Personalization of infliximab therapy 233
- Personalized approaches in immunology 233
- Role of Mannose-binding lectin in personalized medicine 234
- Pharmacogenetics and pharmacogenomics of immunosuppressive agents 234
- Personalized management of patients with lupus erythematosus 234
- Personalized management of pain 235
- Pharmacogenetics/pharmacogenomics of pain 236
- Mechanism-specific management of pain 237
- Preoperative testing to tailor postoperative analgesic requirements 237
- Personalized analgesics 237
- Management of genetic disorders 238
- Personalized treatment of cystic fibrosis 238
- Personalized management of gastrointestinal disorders 238
- Personalized therapy of inflammatory bowel disease 238
- Personalized management of lactose intolerance 239
- Personalized approaches to improve organ transplantation 239
- Personalization of kidney transplantation 240
- Personalization of cardiac transplantation 240
- Prediction of rejection to tailor anti-rejection medications 241
- Personalized immunosuppressant therapy in organ transplants 241
- Role of immunological biomarkers in monitoring grafted patients 242
- Improved matching of blood transfusion 242
- Personalized approach to addiction 243
- Pharmacogenetics of drug addiction 243
- Genetic polymorphism and management of alcoholism 243
- Personalized therapy for smoking cessation 244
- Antidepressant therapy for smoking cessation 244
- Effectiveness of nicotine patches in relation to genotype 244
- Personalized approaches to miscellaneous problems 245
- Hormone replacement therapy in women 245
- Personalized treatment of malaria 245
- Personalized management of renal disease 246
- Gene associated with end-stage renal disease 246
- Personalized care of trauma patients 246
- Personalized anticoagulation 247
- Personalized Hyperbaric oxygen therapy 247
- Personalized preventive medicine 248
- Personalized nutrition 249
- Nutrigenomics 249
- Genomics of vitamin D and calcium supplementation 250
- Nutrigenomics and functional foods 250
- Nutrigenetics and personalized medicine 250
- Nutrigenomics and personalized medicine 251
- Nutrition and proteomics 251
- Personalized diet prescription 252
9. Personalized Therapy of Cancer 254
- Introduction 254
- Challenges of cancer classification 254
- Relationships of technologies for personalized management of cancer 254
- Impact of molecular diagnostics on the management of cancer 255
- Analysis of RNA splicing events in cancer 256
- Analysis of chromosomal alterations in cancer cells 256
- Cancer classification using microarrays 257
- Detection of loss of heterozygosity 257
- Diagnosis of cancer of an unknown primary 258
- Diagnostics for detection of minimal residual disease 258
- DNA repair biomarkers 259
- Fluorescent in situ hybridization 259
- Gene expression profiling 259
- Gene expression profiles predict chromosomal instability in tumors 260
- Isolation and characterization of circulating tumor cells 261
- Modulation of CYP450 activity for cancer therapy 261
- Personalized therapies based on oncogenic pathways signatures 262
- Quantum dot-based test for DNA methylation 262
- Role of molecular imaging in personalized therapy of cancer 263
- Functional diffusion MRI 263
- FDG-PET/CT for personalizing cancer treatment 263
- Image-guided personalized drug delivery in cancer 264
- Tumor imaging and elimination by targeted gallium corrole 264
- Future prospects of molecular imaging in management of cancer 265
- Unraveling the genetic code of cancer 265
- Cancer prognosis 265
- Detection of mutations for risk assessment and prevention 266
- Impact of biomarkers on management of cancer 266
- HER-2/neu oncogene as a biomarker for cancer 267
- L-asparaginase treatment of cancer guided by a biomarker 267
- Oncogene GOLPH3 as a cancer biomarker 267
- Predictive biomarkers for cancer 268
- Sequencing to discover biomarkers to personalize cancer treatment 268
- Systems biology approach to discovery of radiation sensitivity biomarkers
269
- VeraTag"! assay system for cancer biomarkers 269
- Determination of response to therapy 269
- Biomarker-based assays for predicting response to anticancer therapeutics
270
- ChemoFx cell culture assay for predicting anticancer drug response 270
- Ex vivo testing of tumor biopsy for chemotherapy sensitivity 270
- Genomic approaches to predict response to anticancer agents 271
- Gene expression patterns to predict response of cancer to therapy 271
- Genomic analysis of tumor biopsies 271
- Genotype-dependent efficacy of pathway inhibition in cancer 272
- Mutation detection at molecular level 272
- RNA Disruption Assay"! 272
- Role of genetic variations in susceptibility to anticancer drugs 272
- Non-genetic factors for variations in response of cancer cells to drugs
273
- Proteomic analysis of tumor biopsies to predict response to treatment
273
- Real-time apoptosis monitoring 273
- Serum nucleosomes as indicators of sensitivity to chemotherapy 274
- Targeted microbubbles to tumors for monitoring anticancer therapy 274
- PET imaging for determining response to chemotherapy 275
- Tissue systems biology approach to personalized management of cancer 275
- Molecular diagnostics combined with cancer therapeutics 275
- AmpliChip P53 as companion diagnostic for cancer 276
- Aptamers for combined diagnosis and therapeutics of cancer 276
- Monoclonal antibodies for combining diagnosis with therapy of cancer
277
- Targeted cancer therapies 277
- Targeting glycoproteins on cell surface 277
- Targeting pathways in cancer 277
- Targeting receptors and mutations in tumors 278
- Functional antibody-based therapies 278
- Personalized cancer vaccines 279
- Antigen-specific vaccines 279
- Active immunotherapy based on antigen specific to the tumor 280
- Tumor-derived vaccines 280
- MyVax 281
- OncoVAX 281
- Tumor cells treated with dinitrophenyl 281
- Prophage 282
- Melacine 282
- Patient-specific cell-based vaccines 282
- Dendritic cell-based vaccines 282
- Adoptive cell therapy 284
- Combination of antiangiogenic agents with ACT 285
- Genetically targeted T cells for treating B cell malignancies 286
- Genetic engineering of tumor cells 286
- Hybrid cell vaccination 286
- Personalized peptide cancer vaccines 287
- Current status and future prospects of personalized cancer vaccines 287
- Personalized radiation therapy 288
- Role of nanobiotechnology in personalized management of cancer 290
- Design of future cancer therapies 290
- Screening for personalized anticancer drugs 291
- Role of epigenetics in development of personalized cancer therapies 291
- Personalized therapy of cancer based on cancer stem cells 291
- Role of oncoproteomics in personalized therapy of cancer 292
- Cancer tissue proteomics 292
- Role of sequencing in personalized therapy of cancer 292
- Pharmacogenomic-based chemotherapy 293
- Whole genome technology to predict drug resistance 293
- Anticancer drug selection based on molecular characteristics of tumor
293
- Testing microsatellite-instability for response to chemotherapy 294
- Pharmacogenetics of cancer chemotherapy 294
- CYP 1A2 295
- Thiopurine methyltransferase 295
- Dihydropyrimidine dehydrogenase 295
- UGT1A1 test as guide to irinotecan therapy 296
- Role of computational models in personalized anticancer therapy 297
- A computational model of kinetically tailored treatment 297
- Mathematical modeling of tumor mivroenvironments 297
- Molecular profiling of cancer 298
- Drug resistance in cancer 298
- Detection of drug resistance in cancer by metabolic profiling 299
- Determination of chemotherapy response by topoisomerase levels 299
- Anaplastic lymphoma kinase 299
- Management of drug resistance in leukemia 300
- Overexpression of multidrug resistance gene 300
- P53 mutations 300
- A chemogenomic approach to drug resistance 301
- Systems biology approach to personalizing therapy for drug-resistant
cancer 301
- Examples of personalized management of cancer 301
- Personalized management of brain cancer 301
- Biosimulation approach to personalizing treatment of brain cancer 302
- Companion diagnostic for viral gene therapy of brain cancer 302
- Genetics and genomics of brain cancer 302
- Prognosis of glioblastoma multiforme based on its genetic landscape 304
- Molecular diagnostics for personalized management of brain cancer 304
- Personalized chemotherapy of brain tumors 306
- Personalized therapy of oligodendroglial tumors (OTs) 307
- Personalized therapy of neuroblastomas 308
- Personalized therapy of medulloblastomas 308
- Personalized management of germ cell brain tumors 309
- Personalized management of breast cancer 309
- Developing personalized drugs for breast cancer 309
- Gene expression plus conventional predictors of breast cancer 310
- Her2 testing in breast cancer as a guide to treatment 311
- HER2/neu-derived peptide vaccine for breast cancer 313
- Molecular diagnostics in breast cancer 313
- Pharmacogenetics of breast cancer 314
- Proteomics-based personalized management of breast cancer 314
- Predicting response to chemotherapy in breast cancer 315
- Prediction of resistance to chemotherapy in breast cancer 318
- Prediction of adverse reaction to radiotherapy in breast cancer 319
- Prediction of recurrence in breast cancer for personalizing therapy 319
- Prognosistic tests for breast cancer 320
- Racial factors in the management of breast cancer 322
- RATHER consortium to study personalized approach to breast cancer 323
- TAILORx (Trial Assigning Individualized Options for Treatment) 323
- Trends and future prospects of breast cancer research 324
- Understanding tumor diversity in mouse mammary cancer model 324
- Personalized management of ovarian cancer 324
- Early diagnosis of ovarian cancer 324
- Determining response to chemotherapy in ovarian cancer 325
- Recurrent and drug-resistant ovarian cancer 325
- Pathway targeted therapies for ovarian cancer 326
- Personalized management of hematological malignancies 327
- Personalized management of acute lymphoblastic leukemia 327
- Personalized management of acute myeloid leukemia 328
- Personalized management of chronic lymphocytic leukemia 329
- Personalized management of multiple myeloma 329
- Personalized management of myelodysplastic syndrome 330
- Personalized management of lymphomas 331
- Personalized management B cell lymphomas 331
- Personalized vaccine for follicular lymphoma 332
- Companion diagnostic for treatment of lymphoma with Adcentris"! 332
- Personalized management of hepatocellular carcinoma 332
- Personalized management of gastrointestinal cancer 333
- Personalized management of esophageal cancer 333
- Personalized management of gastric cancer 333
- Personalized management of colorectal cancer 334
- A systems biology approach to drug resistance in colorectal cancer 336
- Personalized management of liver cancer 337
- Personalized management of lung cancer 337
- Determination of outcome of EGFR tyrosine kinase inhibitor treatment 337
- Crizotinib for personalized management of NSCLC 339
- Testing for response to chemotherapy in lung cancer 340
- Testing for prognosis of lung cancer 340
- Testing for recurrence of lung cancer 341
- Role of a new classification system in the management of lung cancer 341
- Personalized therapy of NSCLC based on KIF5B/RET fusion oncogene 341
- Personalized management of malignant melanoma 342
- Therapy for inhibiting BRAF mutation in melanoma 342
- Vaccine for malignant melanoma based on heat shock protein 342
- Personalized management of pancreatic cancer 343
- Biomarkers of pancreatic cancer 343
- Histone modifications predict treatment response in pancreatic cancer
344
- Personlized management of prostate cancer 344
- Diagnostics for guiding therapy of prostate cancer 344
- Early detection of cancer recurrence and guiding treatment 345
- Effects of of lifestyle changes shown by gene expression studies 345
- Personalized peptide vaccine for prostate cancer 346
- Future of cancer therapy 346
- Challenges for developing personalized cancer therapies 346
- Cancer Genome Atlas 347
- COLTHERES consortium 347
- Computer and imaging technologies for personalizing cancer treatment
347
- Genomic Cancer Care Alliance 348
- Integrated genome-wide analysis of cancer for personalized therapy 348
- International Cancer Genome Consortium 348
- PREDICT Consortium 349
- Companies involved in developing personalized cancer therapy 350
10. Development of Personalized Medicine 354
- Introduction 354
- Non-genomic factors in the development of personalized medicine 354
- Personalized medicine based on circadian rhythms 354
- Cytomics as a basis for personalized medicine 355
- Intestinal microflora 355
- Gut microbiome compared to human genome 355
- Metabolic interactions of the host and the intestinal microflora 356
- Role of drug delivery in personalized medicine 356
- Personalized approach to clinical trials 357
- Use of Bayesian approach in clinical trials 357
- Individualzing risks and benefits in clinical trials 357
- Clinical trials of therapeutics and companion diagnostics 358
- Players in the development of personalized medicine 358
- Personalized Medicine Coalition 359
- European Personalized Medicine Diagnostics Association 360
- Role of pharmaceutical industry 360
- Production and distribution of personalized medicines 360
- Role of biotechnology companies 361
- Role of life sciences industries 361
- Role of molecular imaging in personalized medicine 362
- Molecular imaging for personalized drug development in oncology 362
- Molecular imaging and CNS drug development 364
- Companies involved in molecular imaging 365
- Role of the clinical laboratories 365
- Role of the US government in personalized medicine 366
- Department of Health and Human Services and personalized medicine 367
- Agency for Healthcare Research and Quality 368
- Comparative effectiveness research 368
- Role of the US Government agencies in personalized medicine 370
- NIH's Roadmap Initiative for Medical Research 370
- NIH and personalized medicine 370
- NIH collaboration with the FDA 371
- NIH and Genetic Testing Registry 371
- National Institute of General Medical Sciences 371
- National Institute of Standards and Technology 373
- Role of the Centers for Disease Control 374
- Role of academic institutions in the US and Canada 374
- Clinical Proteomics Program of NCI & FDA 374
- Coriell Personalized Medicine Collaborative"! 374
- Delaware Valley Personalized Medicine Project 375
- Duke University Medical Center and genomic medicine 375
- Evaluation of genetic tests and genomic applications 376
- Ignite Institute 377
- Indiana University Institute for Personalized Medicine 377
- Institute of Medicine's role in personalized medicine 377
- Jackson Laboratory for Genomic Medicine 378
- Johns Hopkins Center for Personalized Cancer Medicine Research 378
- Mayo Clinic's Center for Individualized Medicine 378
- Mt. Sinai Medical Center's Personalized Medicine Research Program 379
- P4 Medicine Institute 379
- Personalized Medicine Partnership of Florida 379
- Personalized medicine at Ontario Institute for Cancer Research 380
- Personalized oncology at Massachusetts General Hospital 382
- Personalized oncology at Oregon Health & Science University 382
- Pharmacogenetics Research Network and Knowledge Base 382
- Quebec Center of Excellence in Personalized Medicine 383
- Southeast Nebraska Cancer Center's Personalized Medicine Network 383
- Stanford Center for Genomics and Personalized Medicine 383
- UNC Institute for Pharmacogenomics and Individualized Therapy 383
- Wisconsin Genomics Initiative 384
- Role of academic collaborations with companies 384
- New York Genome Center 384
- Role of healthcare organizations and hospitals 385
- Signature Genetics 385
- Role of the medical profession 385
- The American Medical Association and personalized medicine 385
- Education of the physicians 386
- Off-label prescribing and personalized medicine 386
- Medical education 386
- Public attitude towards personalized medicine 387
- Role of genetic banking systems and databases 387
- Role of biobanks in development of personalized medicine 388
- UK Biobank 388
- Biobanking and development of personalized medicine in EU 388
- CARTaGENE for biobanks in Canada 389
- Personalized medicine based on PhysioGenomics"! technology 389
- Role of bioinformatics in development of personalized medicine 390
- Exploration of disease-gene relationship 391
- Biosimulation techniques for developing personalized medicine 391
- Health information management 392
- Electronic health records 392
- Linking patient medical records and genetic information 393
- Management of personal genomic data 394
- Use of EMRs for genetic research 394
- Personalized prognosis of disease 395
- Integration of technologies for development of personalized medicine
395
- Global scope of personalized medicine 396
- Personalized medicine in the developed countries 396
- Personalized medicine in the US 396
- Personalized medicine in the EU 397
- UK National Health Service and medical genetics 397
- Personalized medicine in Germany 398
- Personalized medicine in the developing countries 398
- Advantages and limitations of personalized medicine 399
- Limitations of personalized medicine 400
- Future of personalized medicine 401
- Ongoing genomic projects 401
- Understanding the genetic basis of diseases 401
- Personal Genome Project 402
- Genome-wide association studies 402
- The 1000 Genomes Project 403
- Genomics of aging in a genetically homogeneous population 403
- Translational science and personalized medicine 404
- Translation of genomic research into genetic testing for healthcare 404
- Long-term behavioral effects of personal genetic testing 405
- Personalized predictive medicine 405
- Opportunities and challenges 406
- Prospects and limitations of genetic testing 406
- Genetic testing and concerns about equality of healthcare 407
- Pharmacotyping 407
- Comparative-effectiveness research and personalized medicine 408
- Medicine in the year 2015 408
- Concluding remarks about the future of personalized medicine 409
11. Ethical and Regulatory Aspects of Personalized Medicine 412
- Introduction to ethical issues 412
- Ethical issues of pharmacogenetics 412
- Ethical aspects of genetic information 412
- Ethical issues of whole genome analysis 412
- Ethical aspects of direct-to-consumer genetic services 413
- Privacy issues in personalized medicine 414
- Genetic Information Nondiscrimination Act in the US 415
- Genotype-specific clinical trials 415
- Social issues in personalized medicine 415
- Race and personalized medicine 416
- Regulatory aspects 417
- CLSI guideline for the use of RNA controls in gene expression assays
418
- MicroArray Quality Control Project 418
- Regulatory aspects of pharmacogenetics 419
- Regulation of direct-to-consumer genetic testing 420
- Need for regulatory oversight of DTC 420
- FDA and pharmacogenomics 423
- FDA guidance for pharmacogenomic data submissions 423
- Joint guidelines of the FDA and EU regulators for pharmacogenomics 424
- Pharmacogenomic/pharmacogenetic information in drug labels 424
- FDA guidelines for pharmacogenomics-based dosing 425
- FDA and validation of biomarkers 425
- FDA and predictive medicine 426
- FDA regulation of multivariate index assays 426
- Evaluation of companion diagnostics/therapeutic 428
12. Commercial Aspects of Personalized Medicine 430
- Introduction 430
- Perceived financial concerns 430
- Personalized medicine and orphan drug syndrome 430
- Commercial aspects of pharmacogenomics 430
- Cost of DNA testing 430
- Cost of sequencing the human genome 431
- Cost of genotyping 433
- Cost of pharmacogenomics-based clinical trials 433
- Business development of pharmacogenomic companies 434
- Cost of personalized healthcare 434
- The rising healthcare costs in the US 434
- Reducing healthcare costs by combining diagnostics with therapeutics
435
- Cost-effectiveness of pharmacogenetic testing 435
- Cost-effectiveness of CYP genotyping-based pharmacotherapy 436
- Cost effectiveness of HIV genotyping in treatment of AIDS 436
- Cost-effectiveness of warfarin pharmacogenomics 437
- Lowering the high costs of cancer chemotherapy 437
- Overall impact of personalized medicine on healthcare 438
- Drivers for the development of personalized medicine 438
- Evolution of medicine as a driver for personalized therapy markets 438
- Collaboration between the industry and the academia 439
- Personalized medicine and drug markets 440
- Segmentation of therapeutic drug markets 440
- Reasons for increase of market values of personalized medicines 440
- Growth of markets relevant to personalized medicine 441
- SNP market 441
- Pharmacogenomics 441
- Pharmacogenetics 442
- Pharmacoproteomics 442
- Biochips 442
- Point-of-Care 442
- Markets for personalized medicines according to therapeutic areas 442
- Market for personalized cancer therapy 443
- Markets for personalized medicines according to geographical regions
443
- Market opportunities for personalization of medicine 443
- Impact of personalized medicine on other industries 444
- Strategies for developing and marketing personalized medicine 445
- Education of the public 445
- Role of the Internet in development of personalized medicine 446
- Marketing companion diagnostics for personalized medicine 446
13. References 448
Tables
- Table 1-1: Selected terms relevant to the concept of personalized medicine
22
- Table 1-2: Landmarks in the historical development of personalized
medicine 23
- Table 1-3: Genetic variations in the human genome 28
- Table 2-1: Molecular diagnostic technologies used for personalized
medicine 46
- Table 2-2: Applications of biochip technology relevant to personalized
medicine 65
- Table 2-3: Companies developing haplotying technology 80
- Table 2-4: Technologies for SNP analysis 80
- Table 2-5: A sampling of companies involved in technologies for SNP
genotyping 89
- Table 2-6: Comparison of proteomic and genomic approaches in personalized
medicine 97
- Table 2-7: Selected methods for gene expression profiling 98
- Table 2-8: A selection of companies with gene expression technologies
103
- Table 2-9: Companies involved in companion diagnostics 107
- Table 2-10: Applications of point-of-care diagnosis 108
- Table 2-11: Companies developing point-of-care diagnostic tests 109
- Table 2-12: Companies offering genetic screening tests directly to
consumers 114
- Table 3-1: Pharmacogenetic vs. pharmacogenomic studies 121
- Table 3-2: Enzymes relevant to drug metabolism 123
- Table 3-3: Examples of mutation of the enzyme CYP450 124
- Table 3-4: Frequency distribution of drugs metabolized by major isoforms
of CYP450. 124
- Table 3-5: Commonly prescribed medications, which are metabolized by
CYP2D6 124
- Table 3-6: Polymorphisms in drug target genes that can influence drug
response 130
- Table 3-7: Effect of genetic polymorphisms on disease response to drugs
131
- Table 3-8: Examples of genetically determined adverse reactions to drugs
134
- Table 3-9: Examples of genotyping and phenotyping in some diseases 142
- Table 3-10: Companies with novel molecular toxicology technology 144
- Table 4-1: Role of pharmacogenomics in variable therapy targets 152
- Table 4-2: Role of pharmacogenomics in clinical trials 155
- Table 4-3: Examples of pharmacogenomics-based clinical studies 156
- Table 4-4: Tumor suppressor genes, their chromosomal location, function
and associated tumors. 159
- Table 4-5: Gene polymorphisms relevant to cardiovascular disease
management 160
- Table 4-6: Companies involved in cardiovascular genomics 162
- Table 4-7: A sampling of companies involved in neuropharmacogenomics
164
- Table 8-1: Important therapeutic areas for personalized medicine 184
- Table 8-2: Enzymes that metabolize antipsychotics 196
- Table 8-3: Enzymes that metabolize antidepressants 197
- Table 8-4: Biomarkers of response to interferon-βin multiple
sclerosis 212
- Table 8-5: Genes that cause cardiovascular diseases 214
- Table 9-1: Factors that drive the development of personalized therapy in
cancer 254
- Table 9-2: Impact of molecular diagnostics on the management of cancer
255
- Table 9-3: Targeted therapies in clinical use for cancer 278
- Table 9-4: Clinical trials of personalized cancer vaccines 287
- Table 9-5: Selected companies involved in developing personalized cancer
therapies 350
- Table 10-1: Players in the development of personalized medicine 358
- Table 10-2: Members of the Personalized Medicine Coalition 359
- Table 10-3: Biobanks relevant to personalized medicine 388
- Table 10-4: Role of bioinformatics in the development of personalized
medicine 390
- Table 10-5: Advantages of personalized medicine for the biopharmaceutical
industry 399
- Table 10-6: Advantages of personalized medicine for the patients 399
- Table 10-7: Advantage of personalized medicine for the physicians 400
- Table 10-8: Advantage of personalized medicine for the healthcare
providers 400
- Table 10-9: Limitations of personalized medicine 400
- Table 10-10: Methods of translational science that are relvant to
personalized medicine 404
- Table 10-11: Companies involved in predictive healthcare 406
- Table 11-1: Drugs with genetic information in their labels 424
- Table 12-1: Drivers for the development of personalized medicine 438
- Table 12-2: Growth of markets relevant to personalized medicine 2011-2021
441
- Table 12-3: Markets for personalized medicine according to therapeutic
area 2011-2021 443
- Table 12-4: Markets for personalized medicine in major regions 2011-2021
443
- Table 12-5: Lack of efficacy in current therapy 444
- Table 12-6: Impact of personalized medicine on other industries 444
- Table 12-7: Strategies to develop personalized medicine 445
- Table 12-8: Role of the Internet in development of personalized medicine
446
Figures
- Figure 1-1: Relation of personalized medicine to other technologies 36
- Figure 1-2: Relation of systems pharmacology to personalized medicine
42
- Figure 2-1:Role of sequencing in personalized medicine 64
- Figure 2-2: Role of biochips/microarrays in personalized medicine 66
- Figure 2-3: Affymetrix GeneChip technology 67
- Figure 2-4: Role of CYP450 genotyping in development of personalized
medicine 68
- Figure 2-5: Role of SNPs in personalized medicine 76
- Figure 2-6: A scheme of integrated healthcare and personalized medicine
115
- Figure 3-1: Pharmacogenetics as a link between genotype and phenotype
120
- Figure 3-2: Role of pharmacogenetic technologies in personalized medicine
121
- Figure 4-1: Impact of new technologies at various stages of the drug
discovery process 154
- Figure 4-2: Steps in the application of pharmacogenomics in clinical
trials 156
- Figure 7-1: Role RNAi in development of personalized medicine 182
- Figure 8-1: A scheme of personalized approach to management of
hypertension 220
- Figure 8-2: A scheme of personalized management of pain 235
- Figure 9-1: Relationships of technologies for personalized management of
cancer 255
- Figure 10-1: Integration of technologies for the development of
personalized medicine 396
- Figure 12-1: Evolution of personalized medicine as a market driver 439
Part II
14. Companies Involved in Developing Personalized Medicine 5
Introduction 5 Profiles 5 Collaborations 205
Tables
- Table 14-1: Top five companies involved in personalized medicine 5
- Table 14-2: Selected collaborations of companies in personalized medicine
205
