October 2006
543 Pages
US$ 2,200 (electronic)

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 2010.

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 2005-2015.

Profiles of 195 companies involved in developing technologies for personalized medicines, along with 376 collaborations are included in the part II of the report. Finally the bibliography contains over 400 selected publications cited in the report.The report is supplemented by 53 tables and 15 figures.

T A B L E O F C O N T E N T S
0. Executive Summary .............................................................................. 15
1. Basic Aspects........................................................................................ 17
Definition of personalized medicine ................................................................................17
Historical evolution of medical concepts .........................................................................18
Basics technologies for developing personalized medicine ..............................................20
Conventional medicine versus personalized medicine ......................................................22
Sequencing of the human genome..................................................................................22
Role of variations in human genome ................................................................................ 22
Single nucleotide polymorphisms .................................................................................... 22
Insertions and deletions in the human genome ................................................................. 23
Large scale variation in human genome ........................................................................... 23
Mass analysis of DNA from whole populations ................................................................... 24
Role of genetics in future approaches to healthcare ........................................................24
Genetic medicine ......................................................................................................... 24
Human disease and genes ............................................................................................. 25
Role of genetics in development of personalized medicines .................................................. 25
Genetic databases................................................................................................... 25
Genetic epidemiology............................................................................................... 26
Limitations of medical genetics and future prospects..................................................... 26
Role of systems biology in personalized medicine ...........................................................27
A personalized approach to environmental factors in disease ..........................................27
Reclassification of diseases............................................................................................28
2. Molecular Diagnostics in Personalized Medicine ................................... 29
Introduction..................................................................................................................29
Molecular diagnostic technologies ..................................................................................29
Direct dideoxy DNA sequencing (DDS) ............................................................................. 30
Single-stranded conformation polymorphism (SSCP) analysis .............................................. 30
Heteroduplex analysis (HA) ........................................................................................... 30
The WAVE System ....................................................................................................... 31
DirectLinear™ Analysis .................................................................................................. 31
Denaturing high-performance liquid chromatography (DHPLC) ............................................. 31
Denaturing Gradient Gel electrophoresis (DGGE) ............................................................... 31
Chemical cleavage mismatch (CCM) ................................................................................ 32
Multiplex Allele-Specific Diagnostic Assay ......................................................................... 32
Representational oligonucleotide microarray analysis.......................................................... 32
Cleavase Fragment Length Polymorphism (CFLP)............................................................... 32
Restriction fragment length polymorphism (RFLP).............................................................. 32
Arrayed primer extension (APEX) .................................................................................... 33
Enzymatic Mutation Detection (EMD) ............................................................................... 33
T cells and molecular diagnosis ...................................................................................... 33
The chorioallantoic membrane assay ............................................................................... 34
Sequencing................................................................................................................. 34
Multiplex DNA sequencing......................................................................................... 34
Sequencing in microfabricated high-density picoliter reactors.......................................... 35
Whole genome sequencing ............................................................................................ 35
Biochips and microarrays ...............................................................................................35
Application of biochip technology in developing personalized medicine................................... 35
Standardizing the microarrays........................................................................................ 37
Biochip technologies ..................................................................................................... 37
GeneChip............................................................................................................... 37
AmpliChip CYP450 ................................................................................................... 37
Microfluidics................................................................................................................ 39
Lab-on-a-chip......................................................................................................... 40
Micronics' microfluidic technology............................................................................... 40
LabCD................................................................................................................... 40
Microfluidic automated DNA analysis using PCR ............................................................ 40
Integrated microfluidic bioassay chip .......................................................................... 41
Electronic detection of nucleic acids on microarrays ........................................................... 41
Strand displacement amplification on a biochip ................................................................. 41
Rolling circle amplification on DNA microarrays ................................................................. 42
Universal DNA microarray combining PCR and ligase detection reaction ................................. 42
Protein biochips ........................................................................................................... 42
ProteinChip ............................................................................................................ 43
LabChip for protein analysis ...................................................................................... 43
TRINECTIN proteome chip ........................................................................................ 44
- 4 -
Protein expression microarrays.................................................................................. 44
Microfluidic devices for proteomics-based diagnostics .................................................... 45
New developments in protein chips ............................................................................ 45
Protein chips for personalized medicine ....................................................................... 46
SNP genotyping .............................................................................................................46
Haplotyping ................................................................................................................ 47
Haplotype Specific Extraction .................................................................................... 47
HapMap project ...................................................................................................... 48
Predictingdrug response with HapMap ......................................................................... 49
Companies developing haplotyping technology ............................................................. 49
Technologies for SNP analysis ........................................................................................ 49
Biochip and microarray-based detection of SNPs................................................................ 50
SNP genotyping by MassARRAY ................................................................................. 50
Biochip combining BeadArray and ZipCode technologies ................................................. 51
SNP-IT primer-extension technology........................................................................... 51
OmniScan SNP genotyping........................................................................................ 52
Affymetrix Variation Detection Arrays ......................................................................... 52
Use of NanoChip for detection of SNPs ........................................................................ 52
DNA sequencing .......................................................................................................... 52
Electrochemical DNA probes .......................................................................................... 53
Single base extension-tag array ..................................................................................... 53
Laboratory Multiple Analyte Profile .................................................................................. 53
PCR-CTPP (confronting two-pair primers) ......................................................................... 54
SNP genotyping on a genome-wide amplified DOP-PCR template.......................................... 54
TaqMan real-time PCR .................................................................................................. 54
Non-Enzymatic Amplification Technology.......................................................................... 55
SNP genotyping with gold nanoparticle probes .................................................................. 55
Locked nucleic acid ...................................................................................................... 55
Molecular inversion probe based assays ........................................................................... 56
Pyrosequencing ........................................................................................................... 56
Reversed enzyme activity DNA interrogation test............................................................... 57
Zinc finger proteins ...................................................................................................... 57
UCAN method (Takara Biomedical).................................................................................. 57
Mitochondrial SNPs....................................................................................................... 58
Limitations of SNP in genetic testing................................................................................ 58
Concluding remarks on SNP genotyping ........................................................................... 58
Companies involved in developing technologies/products for SNP analysis ............................. 59
Impact of SNPs on personalized medicine......................................................................... 60
Optical Mapping.............................................................................................................61
Role of nanobiotechnology in molecular diagnostics........................................................61
Role of biomarkers in personalized medicine ..................................................................62
Biomarkers for diagnostics............................................................................................. 62
Biomarkers for drug development ................................................................................... 63
Application of proteomics in molecular diagnosis ............................................................63
Proteomic strategies for biomarker identification ............................................................... 63
Proteomic technologies for detection of biomarkers in body fluids .................................... 64
Protein patterns........................................................................................................... 64
Layered Gene Scanning ................................................................................................ 64
Comparison of proteomic and genomic approaches in personalized medicine .......................... 65
Gene expression profiling ..............................................................................................66
DNA microarrays ......................................................................................................... 66
Analysis of single-cell gene expression............................................................................. 67
Gene expression profiling based on alternative RNA splicing ................................................ 67
Whole genome expression array ..................................................................................... 68
Tangerine™ expression profiling ..................................................................................... 69
Gene expression analysis on biopsy samples..................................................................... 69
Serial analysis of gene expression (SAGE) ........................................................................ 69
Multiplexed Molecular Profiling........................................................................................ 70
Gene expression analysis using competitive PCR and MALDI TOF MS..................................... 70
Monitoring in vivo gene expression by magnetic resonance imaging ...................................... 71
Companies involved in gene expression analysis ................................................................ 71
Monitoring in vivo gene expression by molecular imaging ...............................................72
Molecular imaging and personalized medicine ................................................................72
Glycomics-based diagnostics..........................................................................................72
Combination of diagnostics and therapeutics ..................................................................73
Companies combining diagnostics and therapeutics............................................................ 73
Point-of-care diagnosis ..................................................................................................74
Companies developing point-of-care diagnostic technologies................................................ 75
Point-of-care diagnosis of infections ................................................................................ 77
Advantages versus disadvantages of point-of-care diagnosis ............................................... 77
Future prospects of point-of-care diagnosis ...................................................................... 78
Role of diagnostics in integrated healthcare ...................................................................78
Concept of integrated healthcare .................................................................................... 78
Components of integrated healthcare .............................................................................. 79
Screening .............................................................................................................. 79
Disease prediction ................................................................................................... 79
Early diagnosis ....................................................................................................... 79
Prevention ............................................................................................................. 79
Therapy based on molecular diagnosis ........................................................................ 79
Monitoring of therapy............................................................................................... 80
Advantages and limitations of integrated healthcare........................................................... 80
Commercially available systems for integrated healthcare ................................................... 80
Future of molecular diagnostics in personalized medicine ...............................................82
3. Pharmacogenetics ................................................................................ 83
Basics of pharmacogenetics ...........................................................................................83
Role of molecular diagnostics in pharmacogenetics.........................................................84
Role of pharmacogenetics in pharmaceutical industry .....................................................84
Study of the drug metabolism and pharmacological effects.................................................. 85
Causes of variations in drug metabolism .......................................................................... 85
Enzymes relevant to drug metabolism ............................................................................. 85
Pharmacogenetics of phase I metabolism......................................................................... 86
CYP450 ................................................................................................................. 86
P450 CYP 2D6 inhibition by selective serotonin reuptake inhibitors................................... 88
Lansoprazole and cytochrome P450 ............................................................................ 88
Glucose-6-phosphate dehydrogenase.......................................................................... 89
Pharmacogenetics of phase II metabolism........................................................................ 89
N-Acetyltransferase................................................................................................. 89
Uridine diphosphate-glucuronosyltransferase ............................................................... 90
Measurement of CYP isoforms ........................................................................................ 90
Polymorphism of drug transporters ................................................................................. 91
Genetic variation in drug targets..................................................................................... 91
Polymorphisms of kinase genes ................................................................................. 92
Effect of genetic polymorphisms on disease response to drugs ............................................. 92
Ethnic differences in drug metabolism ............................................................................. 93
Gender differences in pharmacogenetics .......................................................................... 93
Role of pharmacogenetics in drug safety.......................................................................... 94
Adverse drug reactions ............................................................................................ 94
Malignant hyperthermia ........................................................................................... 95
Therapeutic drug monitoring, phenotyping, and genotyping................................................. 96
Therapeutic drug monitoring ..................................................................................... 96
Phenotyping........................................................................................................... 96
Genotyping ............................................................................................................ 97
Genotyping vs phenotyping....................................................................................... 98
Phenomics.................................................................................................................. 98
Limitations of genotype-phenotype association studies .................................................. 99
Molecular toxicology in relation to personalized medicines ................................................... 99
Toxicogenomics ...................................................................................................... 99
Companies involved in molecular toxicology................................................................100
Gene expression studies ..........................................................................................101
Transcriptome profiling studies .................................................................................101
Genomics and the prediction of xenobiotic toxicity .......................................................101
Pharmacogenetics in clinical trials ..................................................................................102
Postmarketing pharmacogenetics...................................................................................102
Clinical implications of pharmacogenetics..................................................................... 103
Examples of use of pharmacogenetics in clinical pharmacology ...........................................103
Linking pharmacogenetics with pharmacovigilance............................................................104
Recommendations for the clinical use of pharmacogenetics ................................................105
Limitations of pharmacogenetics .................................................................................. 105
Academic research in pharmacogenetics ...................................................................... 106
Future role of pharmacogenetics in personalized medicine ............................................ 106
4. Pharmacogenomics............................................................................. 107
Introduction................................................................................................................ 107
Basics of pharmacogenomics ....................................................................................... 107
Pharmacogenomics and drug discovery ........................................................................ 107
Preclinical prediction of drug efficacy.........................................................................109
Pharmacogenomics and clinical trials ........................................................................... 109
Impact of genetic profiling on clinical studies ...................................................................111
Limitations of the pharmacogenomic -based clinical trials ....................................................112
Pharmacogenomic aspects of major therapeutic areas .................................................. 112
Oncogenomics............................................................................................................112
Oncogenes............................................................................................................113
Tumor suppressor genes .........................................................................................113
Cardiogenomics..........................................................................................................114
Neuropharmacogenomics .............................................................................................116
Pharmacogenomics of Alzheimer's disease ..................................................................117
Pharmacogenomics of depression..............................................................................117
Pharmacogenomics of schizophrenia ..........................................................................118
Companies involved in neurogenomics-based drug discovery .........................................118
5. Role of Pharmacoproteomics .............................................................. 121
Basics of proteomics .................................................................................................... 121
Proteomic approaches to the study of pathophysiology of diseases ............................... 121
Single cell proteomics for personalized medicine...............................................................122
Diseases due to misfolding of proteins ............................................................................122
Therapies for protein misfolding................................................................................123
Significance of mitochondrial proteome in human disease ..................................................124
Proteomic technologies for drug discovery and development......................................... 124
Role of proteomics in clinical drug safety.........................................................................124
Toxicoproteomics........................................................................................................124
Application of pharmacoproteomics in personalized medicine ....................................... 126
6. Role of Metabolomics in Personalized Medicine .................................. 127
Metabolomics and metabonomics ................................................................................. 127
Metabolomics bridges the gap between genotype and phenotype .................................. 127
Metabolomics, biomarkers and personalized medicine .................................................. 127
Metabolomic technologies ............................................................................................ 128
Urinary profiling by capillary electrophoresis ....................................................................129
Lipid profiling .............................................................................................................129
Role of metabolomics in biomarker identification and pattern recognition ..............................129
Validation of biomarkers in large-scale human metabolomics studies ...................................130
Pharmacometabonomics .............................................................................................. 130
Metabonomic technologies for toxicology studies.......................................................... 131
Metabonomics/metabolomics a nd personalized nutrition .............................................. 131
7. Personalized Biological Therapies....................................................... 133
Introduction................................................................................................................ 133
Recombinant human proteins ....................................................................................... 133
Therapeutic monoclonal antibodies .............................................................................. 133
Cell therapy ................................................................................................................. 134
Autologous tissue and cell transplants ............................................................................134
Stem cells .................................................................................................................134
Role of stem cells derived from unfertilized embryos ....................................................134
Cloning and personalized cell therapy .............................................................................135
Use of stem cells for drug testing...................................................................................135
Gene therapy ............................................................................................................... 135
Personalized cancer vaccines ....................................................................................... 136
Patient-specific cancer vaccines.....................................................................................136
Personalized cancer vaccines....................................................................................136
Antigen-specific vaccines..............................................................................................136
Autologous cell vaccines...............................................................................................137
Individual cancers are antigenically distinct .....................................................................137
Autologous HSP70-peptide vaccine............................................................................138
Personalized melanoma vaccines ...................................................................................138
Antisense therapy ........................................................................................................ 138
RNA interference ........................................................................................................139
8. Personalized Medicine in Major Therapeutic Areas ............................. 141
Introduction................................................................................................................ 141
Management of viral infections .................................................................................... 142
Management of HIV .....................................................................................................142
Differences in response of the body to HIV .................................................................142
Variations in action of drugs on HIV ...........................................................................142
Role of diagnostic testing in HIV ...............................................................................142
Drug-resistance in HIV ............................................................................................143
Measurement of Replication Capacity.........................................................................144
Prevention of adverse reactions to antiviral drugs ........................................................144
Treatment of hepatitis B...............................................................................................144
Treatment of hepatitis C...............................................................................................145
Psychiatric disorders ................................................................................................... 145
Psychopharmacogenetics..............................................................................................145
COMT genotype and response to amphetamine ...........................................................146
Genotype and response to methylphenidate in children with ADHD .................................146
Personalized antipsychotic therapy.................................................................................146
Personalized antidepressant therapy ..............................................................................148
Pretreatment EEG to predict adverse effects to antidepressants......................................149
Individualization of SSRI treatment ...........................................................................149
Neurological disorders ................................................................................................. 150
Personalized management of Alzheimer's disease .............................................................151
Personalized management of Parkinson's disease .............................................................152
Discovery of subgroup-selective drug targets in PD ......................................................152
Personalized management of Epilepsy ............................................................................153
Choice of the right AED...........................................................................................153
Pharmacogenomics of epilepsy .................................................................................153
Drug resistance in epilepsy ......................................................................................154
Future prospects for epilepsy ...................................................................................155
Personalized management of migraine ............................................................................155
Personalized treatment of multiple sclerosis .....................................................................156
Future prospects for multiple sclerosis .......................................................................157
Cardiovascular disorders .............................................................................................. 157
Role of diagnostics in personalized management of cardiovascular disease ............................157
Testing in coronary heart disease..............................................................................157
Cardiovascular disorders with a genetic component ......................................................158
Gene variant as a risk factor for sudden cardiac death..................................................159
Pharmacogenomics of cardiovascular disorders ................................................................160
Modifying the genetic risk for myocardial infarction ...........................................................160
Management of heart failure .........................................................................................161
Management of hypertension ........................................................................................162
Pharmacogenomics of diuretic drugs..........................................................................162
Pharmacogenomics of ACE inhibitors .........................................................................163
Management of hypertension by personalized approach ................................................163
Pharmacogenetics of lipid-lowering therapies ...................................................................164
Polymorphisms in genes involved in cholesterol metabolism ..........................................164
Role of eNOS gene polymorphisms ............................................................................165
The STRENGTH study.............................................................................................165
Personalized management of women with hyperlipidemia ..............................................166
Thrombotic disorders ...................................................................................................167
Factor V Leiden mutation.........................................................................................167
Anticoagulant therapy.............................................................................................167
Nanotechnology-based personalized therapy of cardiovascular diseases................................168
Concluding remarks .....................................................................................................168
Personalized management of skin disorders ................................................................. 169
Personalized therapy of rheumatoid arthritis ................................................................ 169
DIATSTAT™ anti-cyclic citrullinated peptides in rheumatoid arthritis.....................................170
Personalization of COX-2 inhibitor therapy.......................................................................170
Personalized therapy of asthma ................................................................................... 170
Genetic polymorphism and response to b2-adrenergic agonists............................................171
Genotyping in asthma ..................................................................................................171
Personalized approaches in immunology ...................................................................... 172
Role of Mannose-binding lectin in personalized medicine ....................................................172
Pharmacogenetics and pharmacogenomics of immunosuppressive agents .............................173
Personalized immunosuppressant therapy in organ transplants ...........................................173
Personalized management of pain................................................................................ 174
Pharmacogenetics/pharmacogenomics of pain..................................................................174
Mechanism-specific management of pain.........................................................................175
Preoperative testing to tailor postoperative analgesic requirements......................................175
Personalized analgesics................................................................................................175
Management of genetic disorders ................................................................................. 176
Personalized treatment of cystic fibrosis ..........................................................................176
Personalized management of gastrointestinal disorders ................................................ 176
Personalized therapy of inflammatory bowel disease .........................................................176
Personalized management of lactose intolerance ..............................................................177
Miscellaneous applications ........................................................................................... 177
Genetic polymorphism and management of alcoholism ......................................................177
Personalized therapy for smoking cessation .....................................................................178
Antidepressant therapy for smoking cessation .............................................................178
Effectiveness of nicotine patches in relation to genotype ...............................................178
Hormone replacement therapy in women ........................................................................178
Personalized treatment of malaria ..................................................................................179
Personalized management of renal disease ......................................................................179
Personalization of organ transplantation..........................................................................180
Personalization of kidney transplantation ....................................................................180
Personalization of cardiac transplantation ...................................................................181
Role of immunological biomarkers in monitoring grafted patients....................................181
Personalized care of trauma patients..............................................................................181
Personalized anticoagulation .........................................................................................182
Personalized preventive medicine ................................................................................ 182
Personalized nutrition.................................................................................................. 183
Nutrigenomics............................................................................................................183
Nutrigenomic s and personalized medicine...................................................................184
Personalized diet prescription ........................................................................................184
9. Personalized Therapy of Cancer.......................................................... 187
Challenges of cancer classification..................................................................................187
Impact of molecular diagnostics on the management of cancer...........................................187
Cancer classification using microarrays ......................................................................188
Detection of loss of heterozygosity............................................................................189
Analysis of RNA splicing events in cancer....................................................................189
Analysis of chromosomal alterations in cancer cells ......................................................190
eTag assay system for cancer biomarkers...................................................................190
Fluorescent in situ hybridization................................................................................190
Gene expression profiling ........................................................................................190
Gene expression profiles predict chromosomal instability in tumors.................................192
Diagnosis of cancer of an unknown primary ................................................................192
Personalized therapies based on oncogenic pathways signatures ....................................192
Modulation of CYP450 activity for cancer therapy.........................................................193
Role of molecular imaging in personalized therapy of cancer..........................................193
Diagnostics for detection of minimal residual disease....................................................194
Cancer prognosis ...................................................................................................195
Predictive biomarkers for cancer...............................................................................195
HER-2/neu oncogene as a biomarker for cancer...........................................................195
Detection of mutations for risk assessment and prevention............................................196
Determination of response to therapy.............................................................................196
Biopsy testing of tumors for chemotherapy sensitivity ..................................................196
Genomic analysis of tumor biopsies to predict response to treatment ..............................197
Mutation detection at molecular level.........................................................................197
Proteomic analysis of tumor biopsies to predict response to treatment.............................198
Real-time apoptosis monitoring ................................................................................198
ChemoFx Assay for predicting anticancer drug response................................................198
Serum nucleosomes as indicators of sensitivity to chemotherapy....................................199
Targeted cancer therapies ............................................................................................199
Targeting glycoproteins on cell surface.......................................................................199
Targeting pathways in cancer...................................................................................200
Functional antibody-based therapies ..............................................................................200
Personalized radiation therapy ......................................................................................201
Molecular diagnostics combined with cancer therapeutics...................................................202
Aptamers for combined diagnosis and therapeutics of cancer.........................................202
Role of nanobiotechnology in personalized management of cancer.......................................203
Design of future cancer therapies ..................................................................................204
Screening for personalized anticancer drugs ...............................................................204
Role of epigenetics in development of personalized cancer therapies ...............................204
Role of oncoproteomics in personalized therapy of caner....................................................205
Cancer tissue proteomics.........................................................................................205
Pharmacogenomic-based chemotherapy .........................................................................206
Whole genome technology to predict drug resistance....................................................206
Anticancer drug selection based on molecular characteristics of tumor.............................206
Testing microsatellite-instability for response to chemotherapy ......................................207
Pharmacogenetics of cancer chemo therapy......................................................................207
CYP 1A2 ...............................................................................................................208
Thiopurine methyltransferase...................................................................................208
Dihydropyrimidine dehydrogenase ............................................................................209
UGT1A1 test as guide to irinotecan therapy ................................................................209
Role of computational models in personalized anticancer therapy ........................................210
Drug resistance in cancer.............................................................................................210
Detection of drug resistance in cancer by metabolic profiling..........................................211
GRP78 as a predictor for chemoresponsiveness of breast cancer.....................................211
Drug resistance in colorectal cancer...........................................................................211
Management of drug resistance in leukemia ................................................................212
Overexpression of multidrug resistance gene ..............................................................212
P53 mutations .......................................................................................................213
A chemogenomic approach to drug resistance.............................................................213
Examples of personalized management of cancer .............................................................213
Personalized management of breast cancer ................................................................213
Personalized management of ovarian cancer...............................................................218
Personalized management of acute leukemias .............................................................219
Personalized management of chronic lymphocytic leukemia ...........................................220
Personalized management of multiple myeloma...........................................................221
Personalized management of myelodysplasia ..............................................................222
Personalized management of malignant melanoma ......................................................222
Personalized management of esophageal cancer..........................................................222
Personalized management of colorectal cancer............................................................223
Personalized management of lung cancer ...................................................................224
Personlized management of prostate cancer ...............................................................226
Personalized management of brain cancer ..................................................................226
Personalized therapy of neuroblastomas.....................................................................229
Future of cancer therapy ..............................................................................................230
Challenges for developing personalized cancer therapies ...............................................230
The Cancer Genome Project.....................................................................................230
Companies involved in developing personalized cancer therapy ...........................................231
10. Development of Personalized Medicine....................................... 233
Introduction................................................................................................................ 233
Non-genomic factors in the development of personalized medicine ............................... 233
Personalized medicine based on circadian rhythms ............................................................233
Cytomics as a basis for personalized medicine..................................................................234
Intestinal microflora ....................................................................................................234
Gut microbiome compared to human genome .............................................................234
Metabolic interactions of the host and the intestinal microflora .......................................235
Role of drug delivery in personalized medicine .................................................................235
Personalized approach to clinical trials ............................................................................235
Use of Bayesian approach in clinical trials ...................................................................235
Individualzing risks and benefits in clinical trials ..........................................................236
Players in the development of personalized medicine .................................................... 236
Personalized Medicine Coalition .....................................................................................237
Role of pharmaceutical industry .....................................................................................238
Production and distribution of personalized medicines ...................................................238
Role of biotechnology companies ...................................................................................239
Role of life sciences industries .......................................................................................239
Role of molecular imaging in personalized medicine ..........................................................240
Molecular imaging for personalized drug development in oncology ..................................240
Molecular imaging and CNS drug development ............................................................242
Companies involved in molecular imaging...................................................................242
Role of the clinical laboratories ......................................................................................243
Role of universities and government support....................................................................243
Roadmap Initiative for Medical Research ....................................................................243
Development of products for personalized medicine at the NIH ......................................244
The National Clinical Genomics Initiative ....................................................................244
Genomic-Based Prospective Medicine Project ..............................................................245
Pharmacogenetics Research Network and Knowledge Base ............................................245
Clinical Proteomics Program .....................................................................................246
Southeast Nebraska Cancer Center's Personalized Medicine Network ...............................246
Role of healthcare organizations and hospitals .................................................................246
Signature Genetics.................................................................................................247
The Mayo Clinic genetic database..............................................................................247
Role of the medical profession .......................................................................................247
Education of the healthcare professionals ...................................................................247
Medical education...................................................................................................248
Role of genetic banking systems and databases............................................................ 248
Role of biobanks in development of personalized medicine .................................................248
UK Biobank................................................................................................................249
Personalized medicine based on PhysioGenomics™ technology............................................250
Role of bioinformatics in development of personalized medicine ................................... 250
Exploration of disease-gene relationship .........................................................................251
Health information management....................................................................................252
Electronic medical records .......................................................................................252
Linking patient medical records and genetic information................................................252
Management of personal genomic data......................................................................253
Personalized prognosis of disease ..................................................................................253
Integration of technologies for development of personalized medicine ..................................253
Global scope of personalized medicine.......................................................................... 254
Personalized medicine in the developed countries .............................................................254
NIH initiatives to determine genetic causes of disease ..................................................254
Personalized medicine in the US ...............................................................................255
Personalized medicine in the EU................................................................................255
UK National Health Service and medical genetics.........................................................256
Personalized medicine in the developing countries ............................................................256
Advantages and limitations of personalized medicine .................................................... 257
Future of personalized medicine ................................................................................... 259
Understanding the genetic basis of diseases ....................................................................259
Personal Genome Project..............................................................................................259
Genome-wide association studies...................................................................................259
Personalized predictive medicine....................................................................................260
Opportunities and challenges ........................................................................................261
Pharmacotyping..........................................................................................................261
Medicine in the year 2010 ............................................................................................261
Concluding remarks about the future of personalized medicine............................................262
11. Ethical and Regulatory Aspects of Personalized Medicine........... 265
Introduction to ethical issues....................................................................................... 265
Ethical issues of pharmacogenetics............................................................................265
Genotype-specific clinical trials .................................................................................265
Social issues in personalized medicine .......................................................................266
Privacy issues in personalized medicine......................................................................266
Race and personalized medicine ...............................................................................266
Regulatory aspects of personalized medicine ................................................................ 268
CLSI guideline for the use of RNA controls in gene expression assays...................................269
Regulatory aspects of pharmacogenetics.........................................................................269
FDA and pharmacogenomics.........................................................................................270
FDA guidance for pharmacogenomic data submissions ..................................................270
Joint guidelines of the FDA and EU regulators for pharmacogenomics..............................271
FDA and validation of biomarkers..............................................................................271
FDA and predictive medicine ....................................................................................272
12. Commercial Aspects of Personalized Medicine............................ 273
Introduction................................................................................................................ 273
Perceived financial concerns .........................................................................................273
Personalized medicine and orphan drug syndrome ............................................................273
Commercial aspects of pharmacogenomics ................................................................... 273
Cost of DNA testing .....................................................................................................273
Cost of sequencing the human genome ...........................................................................274
Cost of genotyping ......................................................................................................274
Cost of pharmacogenomics-based clinical trials ................................................................275
Business development of pharmacogenomic companies .....................................................275
Cost of personalized healthcare .................................................................................... 275
Cost of genetic testing .................................................................................................275
Economics of CYP genotyping-based pharmacotherapy ......................................................276
Cost of personalized medicines ......................................................................................276
The rising healthcare costs in the US .........................................................................276
Lowering the cost of healthcare ................................................................................277
Cost effectiveness of HIV genotyping.........................................................................277
Lowering the high costs of cancer chemotherapy .........................................................277
Reducing the cost incurred by adverse drug reactions .......................................................278
Overall impact of personalized medicine on healthcare ......................................................278
Drivers for the development of personalized medicine .................................................. 278
Evolution of medicine as a driver for personalized therapy markets......................................279
Collaboration between the industry and the academia .................................................. 280
Personalized medicine and drug markets...................................................................... 280
Impact on drug markets...............................................................................................280
Growth of markets relevant to personalized medicine ........................................................281
Pharmacogenomics.................................................................................................281
Pharmacogenetics..................................................................................................281
Pharmacoproteomics ..............................................................................................282
Biochips ...............................................................................................................282
Point-of-Care.........................................................................................................282
Markets for personalized medicines according to therapeutic areas ......................................282
Markets for personalized medicines according to geographical regions ..................................283
Market opportunities for personalization of me dicine .........................................................283
Impact of personalized medicine on other industries .........................................................284
Strategies for developing and marketing personalized medicine ..........................................285
Education of the public ............................................................................................285
Role of the Internet in development of personalized medicine ........................................285
13. References.................................................................................. 287

Tables
Table 1-1: Selected terms relevant to the concept of personalized medicine .................................... 17
Table 1-2: Landmarks in the historic al development of personalized medicine .................................. 18
Table 2-1: Molecular diagnostic technologies used for personalized medicine ................................... 29
Table 2-2: Applications of biochip technology relevant to personalized medicine ............................... 35
Table 2-3: Companies developing haplotying technology .............................................................. 49
Table 2-4: Technologies for SNP analysis ................................................................................... 49
Table 2-5: A sampling of companies involved in technologies for SNP genotyping ............................. 59
Table 2-6: Comparison of proteomic and genomic approaches in personalized medicine..................... 65
Table 2-7: Selected methods for gene expression profiling............................................................ 66
Table 2-8: A selection of companies with gene expression technologies .......................................... 71
Table 2-9: Companies combining molecular diagnostics and therapeutics........................................ 73
Table 2-10: Applications of point-of-care diagnosis ...................................................................... 74
Table 2-11: Companies developing point-of-care diagnostic tests................................................... 75
Table 3-1: Pharmacogenetic vs. pharmacogenomic studies ........................................................... 83
Table 3-2: Enzymes relevant to drug metabolism........................................................................ 86
Table 3-3: Examples of mutation of the enzyme CYP450 .............................................................. 86
Table 3-4: Frequency distribution of drugs metabolized by major isoforms of CYP450........................ 87
Table 3-5: Commonly prescribed medications, which are metabolized by CYP2D6 ............................. 87
Table 3-6: Polymorphisms in drug target genes that can influence drug response ............................. 92
Table 3-7: Effect of genetic polymorphisms on disease response to drugs ....................................... 93
Table 3-8: Examples of genetically determined adverse reactions to drugs ...................................... 95
Table 3-9: Examples of genotyping and phenotyping in some diseases ........................................... 98
Table 3-10: Companies with novel molecular toxicology technology.................................................100
Table 4-1: Role of pharmacogenomics in clinical trials .................................................................110
Table 4-2: Examples of pharmacogenomics-based clinical studies .................................................110
Table 4-3: Tumor suppressor genes, their chromosomal location, function and associated tumors. .....113
Table 4-4: Gene polymorphisms relevant to cardiovascular disease management ............................114
Table 4-5: Companies involved in cardiovascular genomics..........................................................116
Table 4-6: A sampling of companies involved in neuropharmacogenomics ......................................118
Table 8-1: Important therapeutic areas for personalized medicine.................................................141
Table 8-2: Enzymes that metabolize antipsychotics....................................................................148
Table 8-3: Enzymes that metabolize antidepressants..................................................................149
Table 8-4: Genes that cause cardiovascular diseases ..................................................................158
Table 9-1: Factors that drive the development of personalized therapy in cancer.............................187
Table 9-2: Impact of molecular diagnostics on the management of cancer......................................188
Table 9-3: Selected companies involved in developing personalized cancer therapies .......................231
Table 10-1: Players in the development of personalized medicine .................................................236
Table 10-2: Members of the Personalized Medicine Coalition ........................................................237
Table 10-3: Biobanks relevant to personalized medicine ..............................................................249
Table 10-4: Role of bioinformatics in the development of personalized medicine ..............................251
Table 10-5: Advantages of personalized medicine for the biopharmaceutical industry .......................257
Table 10-6: Advantages of personalized medicine for the patients.................................................257
Table 10-7: Advantage of personalized medicine for the physicians ...............................................257
Table 10-8: Limitations of personalized medicine .......................................................................258
Table 10-9: Companies involved in predictive healthcare.............................................................260
Table 12-1: Drivers for the development of personalized medicine ................................................278
Table 12-2: Growth of markets relevant to personalized medicine 2005-2015 .................................281
Table 12-3: Markets for personalized medicine according to therapeutic area 2005-2015 ..................283
Table 12-4: Markets for personalized medicine according to major geographical regions ...................283
Table 12-5: Lack of efficacy in current therapy ..........................................................................284
Table 12-6: Impact of personalized medicine on other industries ..................................................284
Table 12-7: Strategies to develop personalized medicine .............................................................285
Table 12-8: Role of the Internet in development of personalized medicine ......................................285

Figures
Figure 1-1: Relation of personalized medicine to other technologies ............................................... 21
Figure 2-1: Role of biochips/microarrays in personalized medicine ................................................. 36
Figure 2-2: Affymetrix GeneChip technology .............................................................................. 38
Figure 2-3: Role of CYP450 genotyping in development of personalized medicine.............................. 39
Figure 2-4: Role of SNPs in personalized medicine....................................................................... 46
Figure 2-5: A scheme of integrated healthcare and personalized medicine ....................................... 78
Figure 3-1: Role of pharmacogenetic technologies in personalized medicine ..................................... 84
Figure 4-1: Impact of new technologies at various stages of the drug discovery process ...................108
Figure 4-2: Steps in the application of pharmacogenomics in clinical trials ......................................110
Figure 7-1: Role RNAi in development of personalized medicine....................................................140
Figure 8-1: A hypothetical personalized medicine approach to management of hypertension..............164
Figure 9-1: Schematic role of proteomics in personalized management of cancer.............................205

Figure 10-1: enTrust Genetic Banking System of First Genetic Trust ..............................................249
Figure 10-2: Integration of technologies for the development of personalized medicine ....................254
Figure 12-1: Evolution of personalized medicine as a market driver...............................................279


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