Biomarkers - Technologies,markets and companies

Keywords : biomarker, cancer biomarker, molecular imaging, proteomic, gene expression, biomarker discovery, bioinformatic, protein biomarker, genetic, protein expression, pharmacogenomic, systems biology, nanobiochip, Protein biochip, pharmacogenetic, biochip, stem cell biomarker, cytogenetic, Tissue microarray, RNA, transcriptomic, Tumor endothelial marker, COLD-PCR, sequencing, telomere

This report follows the broad definition of a biomarker as a characteristic that can be objectively measured and evaluated as an indicator of normal biological or pathogenic processes as well as pharmacological responses to a therapeutic intervention. Tests based on biomarkers have been around for more than half a century, but interest in their application for diagnostics and drug discovery as well as development has increased remarkably since th...

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This report follows the broad definition of a biomarker as a characteristic that can be objectively measured and evaluated as an indicator of normal biological or pathogenic processes as well as pharmacological responses to a therapeutic intervention. Tests based on biomarkers have been around for more than half a century, but interest in their application for diagnostics and drug discovery as well as development has increased remarkably since the beginning of the 21st century. This report describes different types of biomarkers and their discovery using various “-omics” technologies such as proteomics and metabolomics. Molecular diagnostics technologies are used for the discovery of biomarkers and new tests are also based on biomarker.

Currently the most important applications of biomarkers are in drug discovery and development. The role of biomarkers in various therapeutic areas particularly cancer, cardiovascular diseases and disorders of the central nervous system, is described. Biomarkers are useful not only for diagnosis of some of these diseases but also for understanding the pathomechanism as well as a basis for development of therapeutics.

Biomarkers will facilitate the combination of therapeutics with diagnostics and will thus play an important role in the development of personalized medicine. Biomarkers play a role in use of pharmacogenetics, pharmacogenomics and pharmacoproteomics for development of personalized medicine.

Many of the regulatory issues concerning biomarkers are related to genomics, proteomics, molecular diagnostics and pharmacogenomics/pharmacogenetics. Validation of biomarkers and their role in clinical trials is discussed.

Biomarker markets are estimated from 2011 to 2021 according to share of markets for various technologies and applications: proteomics, metabolomics, molecular diagnostics, drug discovery, clinical trials, and bioinformatics. Market values are further split according to therapeutic applications and major geographical areas. Unfulfilled needs in biomarkers are identified as well as the drivers for biomarker markets. Challenges facing the biomarker industry and strategies for developing biomarker markets are discussed.

A large number of companies with varying technical backgrounds are involved in biomarkers and 279 of these are profiled in part 2 of the report with classification into various categories.These also include major pharmaceutical companies. There is tabulation of 518 collaborations between companies and additional academic collaborations are mentioned in the individual profiles of companies. The report is supplemented by 1,000 references, 66 tables and 13 figures

Genomics Industry

TABLE OF CONTENTS

0. Executive Summary 21
1. Introduction 23
Definitions 23
Historical aspects of biomarkers 23
Classification of biomarkers 24
Biological marker as response to therapeutic intervention 25
Pharmacokinetic/pharmacodynamics biomarkers 25
Predictive biomarkers 25
Valid biomarkers 26
Types of biomarkers 26
Genes as biomarkers 26
Proteins as biomarkers 27
Proteomics 27
DNA biomarkers 28
Mitochondrial DNA 28
Mitochondrial mutations 28
RNA biomarkers 28
Transcriptomics 29
MicroRNAs 30
Metabolomics 30
Glycomics 30
Single nucleotide polymorphisms 31
Haplotyping 31
Cell biomarkers of disease 32
Stem cell biomarkers 32
Association of stem cell biomarkers with disease 32
Cancer stem cell biomarkers 33
Endoglin as a functional biomarker of stem cells 33
p75NTR as a biomarker to isolate adipose tissue-derived stem cells 33
Protein expression profile as biomarker of stem cells 33
STEMPRO? EZChek? for analysis of biomarkers of hESCs 34
SSEA-4 as biomarker of MSCs 34
Gaseous mediators as biomarkers of disease 34
Autoantibodies as biomarkers of autoimmune diseases 34
Comparison of various types of biomarkers 35
Biomarkers and systems biology 36
Systems biology approach to biomarker identification 37
Relation of biomarkers to other technologies and healthcare 37
Biomarkers and translational medicine 38
Limitations of use of biomarkers in healthcare 38
2. Technologies for Discovery of Biomarkers 41
Introduction 41
The ideal biomarker 41
Genomic technologies 41
Gene expression 41
Whole genome expression array 42
Gene expression profiling on whole blood samples 43
Profiling gene expression patterns of white blood cells 43
Tissue microarrays for study of biomarkers 43
Epigenomic technologies 44
Discovery of methylation biomarkers 44
Proteomic technologies 45
2D GE 46
Biomarker Amplification Filter 47
CellCarta® proteomics platform 47
Isotope-coded affinity tags 48
Liquid chromatography-MS/MS 48
Lucid Proteomics System 48
Magnetics beads for protein biomarker discovery 49
MASStermind™ 49
Mass spectrometry 49
2D PAGE and mass spectrometry 50
Imaging mass spectrometry 50
MALDI mass spectrometry for biomarker discovery 51
Quantitative tandem MS 52
Single-molecule mass spectrometry using a nanopore 52
Requirements for MS-based proteomic biomarker development 53
Protein tomography 53
Protein biochips/microarrays and biomarkers 53
Antibody-based biomarker discovery 54
Detection of biomarkers using peptide array technology 54
Discovery of biomarkers by MAb microarray profiling 54
Protein nanobiochip 55
Gene expression microarray data as a source of protein biomarkers 55
Quantification of protein biomarkers 55
Mass spectrometry for quantification of protein biomarkers 55
Real-time PCR for quantification of protein biomarkers 56
CyTOF for quantification of biomarkers 56
Search for biomarkers in body fluids 56
Challenges and strategies for discovey of protein biomarkers in plasma 57
3-D structure of CD38 as a biomarker 58
BD™ Free Flow Electrophoresis System 58
Isotope tags for relative and absolute quantification 58
Plasma protein microparticles as biomarkers 59
Proteome partitioning 59
Stable isotope tagging methods 60
Technology to measure both the identity and size of the biomarker 60
Targeted proteomic approaches 61
Biomarkers in the urinary proteome 61
Peptides in body fluids and tissues as biomarkers of disease 61
Analysis of peptides in bodily fluids 62
Serum peptidome patterns 62
SISCAPA method for quantitating proteins and peptides in plasma 63
Comparison of proteomic profiling technologies for discovery of biomarkers 63
Verification for interlaboratory reproducibility of protein biomarkers 63
Significance of similar protein biomarkers in different tissues 64
Glycomic technologies 65
Metabolomic technologies 65
Genome-wide association studies for identification of metabolic biomarkers 66
Lipid profiling 66
Mass spectrometry-based kits for discovery of metabolic biomarkers in plasma 66
Role of metabolomics in biomarker identification and pattern recognition 67
Urinary profiling by capillary electrophoresis 67
Validation of biomarkers in large-scale human metabolomics studies 67
Lipidomics 67
Disease biomarkers in breath 68
Portable breath test for volatile organic compounds 68
Detection of breath biomarkers by sensation technology 69
Detection of breath biomarkers optical frequency comb spectroscopy 69
Detection of breath biomarkers by infrared absorption spectroscopy 69
Fluorescent indicators for biomarkers 70
Molecular imaging technologies 70
Computer tomography 70
Magnetic resonance imaging 71
Positron emission tomography 71
Advantages of imaging biomarkers 72
Monitoring in vivo gene expression by molecular imaging 72
Molecular imaging in vivo as a biomarker 72
Challenges and future prospects of molecular imaging 73
Basic research in molecular imaging 73
Imaging intracellular NADH as a biomarker of disease 73
Devices for molecular imaging 74
Imaging biomarkers in clinical trials 74
Molecular imaging in clinical practice 74
Nuclear magnetic resonance 74
Chemical derivatization to enhance biomarker detection by NMR 75
Fluxomics by using NMR 75
Nanobiotechnology 75
Nanomaterials for biolabeling 76
Quantum dot molecular labels 77
Bioconjugated QDs for multiplexed profiling of biomarkers 77
Magnetic nanotags for multipley detection of biomarkers 78
Nanoproteomics and biomarkers 78
High-field asymmetric waveform ion mobility mass spectrometry 78
Nanoparticles for molecular imaging 78
Nanoparticles for discovering biomarkers 79
Nanosensors for measuring biomarkers in blood 79
Nanobiochip sensor technique for analysis of oral cancer biomarkers 80
Nucleoprotein nanodevices for detection of cancer biomarkers 80
Future prospects of application of nanobiotechnology for biomarkers 80
Bioinformatics 81
Biomarker Workflow Guide 81
Analysis of microarray data for selecting useful biomarkers 81
Role of bioinformatics in discovery of protein biomarkers 82
Role of bioinformatics in detection of cancer biomarkers 82
Biomarker databases 83
Gene networks as biomarkers 83
Role of bioinformatics in integrating various data and biomarker discovery 83
Evaluation of biomarker studies 84
3. Biomarkers and Molecular Diagnostics 85
Introduction 85
Molecular diagnostic technologies 85
Polymerase chain reaction 85
Amplification 85
Target selection 86
Detection of amplified DNA 86
Limitations of PCR 86
Real-time PCR systems 87
Limitations of real-time PCR 87
Future applications of real-time qPCR 88
Real-time qPCR for quantification of circulating mtDNA 88
Combined PCR-ELISA 88
Non-PCR methods 89
Linked Linear Amplification 89
Transcription mediated amplification 89
Rapid analysis of gene expression 89
WAVE nucleic acid fragment analysis system 90
DNA probes with conjugated minor groove binder 90
Rolling circle amplification technology 91
Gene-based diagnostics through RCAT 91
RCAT-immunodiagnostics 92
RCAT-biochips 92
RCAT-pharmacogenomics 92
Circle-to-circle amplification 92
Biochips and microarrays 93
Applications of biochips/microarrays 93
Role of biochip/microarrays in discovery of biomarkers 94
Biomarkers and high throughput molecular screening 94
Detection and expression profiling of miRNA 95
Real-time PCR for expression profiling of miRNAs 95
Real-time PCR for expression profiling of miRNAs 95
Use of LNA to explore miRNA 95
Microarrays for analysis of miRNA gene expression 96
4. Biomarkers for Drug Discovery & Development 97
Introduction 97
Biomarker technologies for drug discovery 98
Proteomics-based biomarkers for drug discovery 98
Chemoproteomics 98
Activity-based chemical proteomics 98
Transcriptomics for drug discovery 99
AvalonRx® drug discovery platform 99
Metabolomics for drug discovery 99
Biomarkers and drug safety 100
Biomarkers of adverse drug reactions 100
Applications of biomarkers in drug safety studies 101
Genomic technologies for toxicology biomarkers 101
Proteomic technologies for toxicology biomarkers 102
Metabonomic technologies for toxicology biomarkers 102
Integration of genomic and metabonomic data to develop toxicity biomarkers 102
Toxicology studies based on biomarkers 103
Biomarkers of hepatotoxicity 104
Biomarkers of nephrotoxicity 105
Cardiotoxicity 106
Neurotoxicity 107
Applications of biomarkers for drug development 107
Application of metabonomics/metabolomics for drug development 107
Role of pharmacokinetic/pharmacodynamic biomarkers in drug development 108
Molecular imaging as a biomarker in drug development 109
Molecular imaging in preclinical studies 109
Molecular imaging in clinical trials 110
Prospects of molecular imaging in drug discovery and development 111
Biomarkers in clinical trials 111
NIH recommendations on the use of biomarkers in clinical trials 112
Advantages of biomarkers for drug development 113
Limitations and problems with use of biomarkers in clinical trials 113
Application of biomarkers by the pharmaceutical companies 114
Use of biomarkers in relation to stage of drug discovery and development 115
Drug development in cardiovascular disorders 115
Drug development in neurological disorders 115
Future prospects of biomarker-based drug development 116
The Biomarker Alliance 116
Molecular Libraries and Imaging Roadmap of NIH 117
Biomarkers Consortium 117
Pharmacogenomic biomarker information in drug labels 118
Concluding remarks on the future trends in biomarker development 119
5. Role of Biomarkers in Healthcare 121
Introduction 121
Biomarkers of inflammation 121
ESR and CRP as biomarkers of inflammation 122
Biomarkers of oxidative stress 122
1,4-dihydroxynonane-mercapturic acid 122
Oxidative DNA damage 123
Proteins as biomarkers of oxidative stress in diseases 123
Testing for oxidative stress 123
Biomarkers in metabolic disorders 123
Biomarkers of acute intermittent porphyria 123
Liver X receptors 124
Biomarkers of diabetes mellitus 124
Biomarkers of hyperglycemia 125
Biomarkers of diabetes-associated oxidative stress 125
Biomarkers of inflammation associated with diabetes 126
Biomarkers of renal complications in diabetes mellitus type 2 126
Biomarkers of diabesity 126
Glycosylated hemoglobin in diabetes mellitus 126
Glycated albumin as a biomarker of diabetes mellitus 127
Lack of C-peptide as biomarker of complications of diabetes type 1 127
Serum retinol binding protein 4 as biomarker of insulin resistance 127
Biomarkers of metabolic syndrome 128
Adiponectin 128
Biomarkers in immune disorders 129
Biomarkers relevant to organ transplantation 129
Biomarkers of graft versus host disease 129
Biomarkers of renal allograft failure 130
Biomarkers of renal transplant tolerance 131
Biomarkers of lung transplant rejection 132
Systemic lupus erythematosus 132
Current management and need for biomarkers 132
Role of collaborative efforts and databases of SLE biomarkers 133
C4d-bearing reticulocytes 133
Adiponectin 133
CB-CAPS 133
HMGB1 134
Genetic loci of SLE 134
Epigenetic biomarkers of SLE 134
Biomarkers of musculoskeletal disorders 134
Biomarkers of rheumatoid arthritis 135
Circulating cytokines in RA 135
miRNA biomarkers in RA 135
Serum CRP in RA 136
Assays for biomarkers of RA 136
Biomarkers of spondylarthritis 136
Biomarkers of osteoarthritis 137
Biomarkers of osteoporosis 138
Dual x-ray absorptiometry 139
Bone imaging with quantitative CT and MRI 139
Assays for detection of biomarkers of osteoporosis 139
Biomarkers of osteonecrosis 139
Osteonecrosis in Gaucher’s disease 139
Biomarkers of infectious diseases 139
Application of proteomics for discovering biomarkers of infections 141
Chemokines as biomarkers of infection 141
Circulating CPS-1 as biomarkers of organ damage in sepsis 141
CoQ10 level reduction in septic shock 142
Endotoxin as biomarker of infection 142
Nitric oxide as a biomarker of sepsis 142
Procalcitonin as a guide to antibiotic therapy in infections 143
Soluble urokinase plasminogen activator receptor 144
Systemic inflammatory response syndrome 144
Tuberculosis 144
Conventional diagnosis of tuberculosis 145
Molecular diagnostics for tuberculosis 145
Biomarkers for tuberculosis 146
Biomarkers of pulmonary tuberculosis in the breath 146
Biomarkers of viral infections 146
Viral hepatitis 147
Biomarkers of SARS 149
Biomarkers of HIV 149
Biomarkers in parasitic infections 150
Role of biomarkers in malaria 150
Identification of biomarkers in Schistosomiasis infections 151
Biomarkers of liver disease 151
Breath biomarkers of liver disease 151
Biomarkers of viral hepatitis B and C 152
Biomarkers of liver injury 153
Biomarkers of liver cirrhosis 153
FibroMax 153
Biomarkers of pancreatitis 153
Biomarkers of renal disease 154
Biomarkers of lupus nephritis 154
Biomarkers of diabetic nephropathy 154
Cystatin C as biomarker of glomerular filtration rate (GFR) 155
Estimated GFR and albuminuria as biomarkers of chronic kidney disease 155
Proteomic biomarkers of acute kidney injury 155
Biomarkers of pulmonary diseases 156
Biomarkers of oxidative stress in lung diseases 156
Biomarkers of acute lung injury and respiratory distress syndrome 157
Cytokine/chemokine biomarkers of SARS 157
Plasma biomarkers related to inflammation 157
Urinary NO as biomarker 157
Biomarkers of interstitial lung disease 158
Pulmonary surfactant proteins as biomarkers for lung diseases 158
Serum KL-6 as biomarker of interstitial lung disease 158
Biomarkers of chronic obstructive pulmonary disease 158
Alpha1-antitrypsin gene polymorphisms predisposing to emphysema 159
BNP as a biomarker of chronic pulmonary disease 159
Chromagranin A (CgA) as biomarker of airway obstruction in smokers 159
Gene expression profile in peripheral blood of patients with COPD 159
Increased expression of PIGF as a biomarker of COPD 159
Biomarkers of asthma 160
Biomarker for rhinovirus-induced asthma exacerbation 160
Biomarkers for predicting response to corticosteroid therapy 160
Comparison of biomarkers of asthma and COPD 160
Cytokines as biomarkers of asthma severity 161
Exaled NO as a biomarker of asthma 161
Endothelin-1 in exhaled breath as biomarker of asthma 162
IgE as guide to dosing of omalizumab for asthma 162
Periostin as a biomarker for treatment of asthma with lebrikizumab 162
Biomarkers for cystic fibrosis 163
Biomarkers of pulmonary embolism 163
D-dimer as biomarker of thromboembolism 163
BNP and cTnT as biomarkers of outcome in pulmonary embolism 164
Biomarkers in gynecology and obstetrics 164
Biomarkers of menopause 164
Biomarkers of premenstrual dysphoric disorder 165
Biomarkers of endometriosis 165
Biomarkers for preeclampsia 166
Protein biomarker of preeclampsia in urine 166
Protein biomarkers of preeclampsia in CSF 166
Protein HtrA1 as biomarker for preeclampsia 167
sFlt1 and soluble endoglin as biomarkers of preeclampsia 167
RNA biomarkers 168
Biomarkers of premature birth 168
Biomarkers of oxidative stress in complicated pregnancies 169
Fetal biomarkers in maternal blood 169
Biomarkers for genetic disorders 169
Biomarkers for Down’s syndrome 169
Biomarkers for muscular dystrophy 170
Biomarkers of phenylketonuria 170
Genetic biomarkers for psoriasis 171
Biomarkers of lysosomal storage disorders 171
Biomarkers of aging 172
Effect of calorie restriction on biomarkers of longevity 174
Genes as biomarkers of aging 174
Mitochondrial mutations as biomarkers of aging 174
Telomere attrition as aging biomarker 174
Gene variants as determinants of biological age 175
Genetic signatures of longevity 175
Low serum thyroid hormone level as biomarker of longevity 175
Role of bioinformatics in search for biomarkers of aging 176
Study of biomarkers of aging in a genetically homogeneous population 176
Biomarkers of miscellaneous disorders 176
Biomarkers of inflammatory bowel disease 176
Biomarkers of erectile dysfunction 177
Biomarkers of fever 178
Biomarkers of heat stroke 178
Biomarkers of radiation injury 178
Biomarkers common to multiple diseases 179
Nasal nitric oxide as a biomarker of response to rhinosinusitis therapy 179
Biomarkers and nutrition 179
Biomarkers in nutritional epidemiology 179
Biomarkers of nutritional status 180
Biomarkers of branched chain amino acid status 180
Biomarkers of caloric restriction 180
Biomarkers of malnutrition 181
Proteomic biomarkers and nutrition 181
Vitamin deficiency as biomarker of disease 181
Vitamin D as a biomarker of disease 181
Vitamin B12 deficiency 182
Biomarkers of gene-environmental interactions in human disease 183
6. Biomarkers of Cancer 185
Introduction 185
The ideal biomarker for cancer 185
Single vs multiple biomarkers of cancer 186
Types of cancer biomarkers 186
HER3 as biomarker of cancer 187
DNA repair biomarkers 187
miRNAs as biomarkers in cancer 187
Circulating miRNAs for cancer detection 189
Diagnostic value of miRNA in cancer 189
Biomarkers of epigenetic gene silencing in cancer 189
Immunologic biomarkers of cancer 190
Molecular diagnostic techniques for cancer 190
Technologies for detection of cancer biomarkers 191
Genomic technologies for cancer biomarkers 191
Cold-PCR 191
Genome analysis at the molecular level 192
Sequencing-based approaches for detection of cancer biomarkers 192
Early detection of tumor suppressor gene mutations 192
Biomarkers of PTEN tumor suppressor gene status 193
HAAH as a biomarker for cancer 193
KRAS as a biomarker of cancer 194
Telomerase as a biomarker of cancer 194
Digital karyotyping for cancer biomarkers 194
LigAmp for detection of gene mutations in cancer 195
Mitochondrial DNA as a cancer biomarker 195
Tissue microarrays for study of cancer biomarkers 195
Molecular fingerprinting of cancer 196
Biomarkers of inflammation in cancer 197
Proteomic technologies for detecting biomarkers of cancer 197
2D PAGE 198
Antibody-based detection of protein biomarkers 198
Aptamer-based molecular probes for cancer biomarker discovery 199
Cancer immunomics to identify autoantibody signatures 199
Desorption electrospray ionization for detection of cancer biomarkers 200
Detection of circulating nucleosomes in serum of cancer patients 200
Detection of tumor markers with ProteinChip technology 200
eTag assay system for cancer biomarkers 201
Glycoprotein biomarkers of cancer 201
HER-2/neu oncoprotein as biomarkers for cancer 202
Humoral proteomics 202
Laser capture microdissection 202
Membrane-type serine protease-1 203
Phage display technology 203
Proteomic analysis of cancer cell mitochondria 203
Proteomic technologies for detection of autoimmune biomarkers 204
SELDI-TOF MS 204
Serum proteome analysis for early detection of cancer 204
Triple-quadrupole MS for detection of mutant proteins 205
Targeted MS for validation of cancer biomarkers in plasma 205
Tissue proteomics for discovery of cancer biomarkers 205
Metabolomic biomarkers of cancer 205
Choline phospholipid biomarkers of cancer 206
Hypoxia-inducible factor-1 206
Detection of drug resistance in cancer by metabolic profiling 207
Epitomics for the early detection of cancer 207
Detection of biomarkers of DNA methylation 207
PCR with bisulfite for detecting DNA methylation biomarkers in cancer 209
MDScan? microarray technology 210
Rubicon MethylPlex technology 210
Epigenomics Marker Machine for DNA methylation biomarkers 210
Sequenom’s integrated genetic analysis platform 211
Histone deacetylase 211
Mucins as epigenetic biomarkers in epithelial cancers 211
Nanobiotechnology for early detection of cancer to improve treatment 212
Selective expression of biomarkers by cancer compared with normal tissues 212
Ultrasound radiation to enhance release of a tumor biomarker 212
In vivo imaging of cancer biomarkers 213
Computer tomography 213
Optical systems for in vivo molecular imaging of cancer 213
Positron emission tomography 213
Imaging of tumor oxygenation and microvascular permeability by MRI 214
Xenon-enhanced MRI 214
Kallikrein gene family and cancer biomarkers 214
Circulating cancer cells in blood as biomarkers of cancer 215
Applications of cancer biomarkers 216
Use of biomarkers for cancer classification 216
Cancer classification using microarrays 216
Proteomic classification of cancer 216
Use of biomarkers for early detection of cancer 216
Applications of biomarkers for cancer diagnosis 217
Methylated DNA sequences as cancer biomarkers 217
MicroRNA expression profiling for diagnosis of human cancers 218
MUC4 as a diagnostic biomarker in cancer 218
Applications of biomarkers for cancer diagnosis and therapy 218
Asparagine synthetase as biomarker for therapy with L-asparaginase 219
Peptide-based agents for targeting cancer biomarkers 219
Biomarkers for assessing efficacy of cancer therapy 220
ERCC1-XPF expression as a biomarker of response to chemotherapy 220
P53 expression level as biomarker of efficacy of cancer gene therapy 220
Biomarkers of angiogenesis for developing antiangiogenic therapy 220
Biomarkers of response to antiangiogenic agents 221
Circulating endothelial cells as targets for antiangiogenic drugs 221
Imaging biomarkers for evaluation of antiangiogenic agents 221
Tumor endothelial markers 222
VEGF signaling inhibitors as biomarkers 222
VEGF-PET imaging for analysis of angiogenic changes within a tumor 223
Biomarkers of prognosis in cancer treatment 223
Biomarkers of drug resistance in cancer 223
A systems approach to biomarkers of innate drug resistance 224
Epithelial membrane protein-1 as a biomarker of gefitinib resistance 224
Methylation biomarkers of drug resistance in cancer 224
STAT3 and resistance to cisplatin 225
Biomarkers of radiation therapy for cancer 225
Role of biomarkers in drug development in oncology 225
Molecular imaging of tumor as a guide to drug development 226
Use of PET to assess response to anticancer drugs 227
Use of MRI to assess response to anticancer drugs 227
Biomarkers in plucked hair for assessing cancer therapy 227
Molecular targets of anticancer drugs as biomarkers 228
Safety biomarkers in oncology studies 228
Role of biomarkers in phase I clinical trials of anticancer drugs 228
Biomarkers according to location/type of cancer 229
Bladder cancer biomarkers 229
Detection of FGFR3 mutations in urine for diagnosis of bladder cancer 229
NMP22 BladderChek 229
Urinary telomerase as biomarker for detection of bladder cancer 230
Concluding remarks abut biomarkers of urinary cancer 230
Brain tumor biomarkers 230
14-3-3zeta positive expression as a prognostic biomarker for GBM 231
Biomarkers to predict response to EGFR inhibitors 231
CD133 as biomarker of resistance to radiotherapy 231
Circulating microvesicles as biomarkers 232
CSF protein profiling 232
CSF attractin as a biomarker of malignant astrocytoma 232
Methylation profiling of brain tumors 232
Metabolite biomarkers of brain tumors 233
miRNAs as biomarkers of brain tumors 234
MRI biomarker for response of brain tumor to therapy 234
Multigene predictor of outcome in GBM 234
Neuroimaging biomarkers combined with DNA microarray analysis 235
Receptor protein tyrosine phosphatase ? as biomarker of gliomas 235
Serum protein fingerprinting 235
VEGF-R2 as biomarker of angiogenesis in brain tumors 236
Bone tumor biomarkers 236
Cytogenetics for the study of bone and soft tissue tumors 236
Biomarkers of Ewing’s tumors 236
Role of biomarkers in the diagnosis of bone tumors 237
Breast cancer biomarkers 237
Autoantibody biomarkers of breast cancer 238
Biomarkers of breast cancer in breath 239
Biomarkers for breast cancer in nipple aspiration fluid 239
Circulating nucleic acid biomarkers of breast cancer 239
Flow cytometry for quantification of biomarker expression patterns 239
Plasma proteomics for biomarkers of breast cancer 240
Quantitative realtime PCR assays for biomarker validation 240
Cdk6 as a biomarker of breast cancer 241
Centromere protein-F 241
Carbonic anhydrase IX 241
COX-2 as a biomarker of breast cancer 242
Glycomic biomarkers of breast cancer 242
HER-2/neu oncoprotein 242
High mobility group protein A2 244
Hypermethylated genes as biomarkers of metastatic breast cancer 244
Lipocalin 2 as biomarker of breast cancer progression 244
Long intervening non-coding RNAs 245
Mammaglobin 245
miRNA biomarkers of breast cancer 245
p27 expression as biomarker for survival after chemotherapy 246
Podocalyxin 246
Progranulin as a biomarker of breast cancer 247
Proliferating cell nuclear antigen 247
Protein kinase C as a predictive biomarker of metastatic breast cancer 247
Retinoblastoma tumor suppressor gene as a biomarker 247
Riboflavin carrier protein 248
Risk of invasive cancer after diagnosis of ductal carcinoma in situ 248
Serum CA 15-3 as biomarker of prognosis in advanced breast cancer 249
Suppressor of deltex protein 249
Tumor microenvironment as biomarker of metastasis in breast cancer 249
Type III TGF-? receptor as regulator of cancer progression 249
Diagnostic tests based on breast cancer genes 250
Prognostic role of breast cancer genes 251
Protein biomarkers for breast cancer prevention 252
Biomarkers to evaluate efficacy of chemoprevention 252
Biomarkers of response to chemotherapy of breast cancer 252
Concluding remarks and future prospects of breast cancer biomarkers 253
Cervical cancer biomarkers 253
Gastrointestinal cancer biomarkers 255
Esophageal cancer biomarkers 255
Gastric cancer biomarkers 255
Colorectal cancer biomarkers 256
Head and neck cancer 261
Leukemia biomarkers 262
Chromosome translocations in leukemias 262
DNA methylation biomarkers in leukemia 263
Gene mutations as biomarkers in leukemia 263
Molecular diagnostic techniques for leukemia 263
Proteomic technologies for discovering biomarkers of leukemia 264
Biomarkers of chronic lymphocytic leukemia 264
Biomarkers of chronic myeloid leukemia 265
Biomarkers of drug resistance in leukemia 265
Biomarkers of myelodysplasitic syndromes 266
Lymphoma biomarkers 266
Liver cancer biomarkers 266
Lung cancer biomarkers 267
Autoantibodies as biomarkers in lung cancer 268
Biomarkers associated with neuroendocrine differentiation in NSCLC 269
Biomarkers of chronic inflammation in lung cancer 269
Biomarkers for predicting sensitivity to chemotherapy in lung cancer 269
Biomarkers for prediction of sensitivity to EGFR inhibitors 270
Circulating tumor cells as biomarkers 271
Gene expression profiling for biomarkers of lung cancer 271
Methylation biomarkers of lung cancer 272
miRNA biomarkers in lung cancer 272
Proteomic biomarkers in exaled breath condensate 273
Serum protein biomarkers of lung cancer 273
tNOX as biomarker of lung cancer 274
Tumor-derived DNA and RNA markers in blood 274
Volatile organic compounds in the exhaled breath 274
Malignant pleural mesothelioma 275
Melanoma biomarkers 275
Nasopharyngeal carcinoma biomarkers 277
Proteomic biomarkers of nasopharyngeal cancer 278
miRNA biomarkers of nasopharyngeal carcinoma 278
Oral cancer biomarkers 278
Ovarian cancer biomarkers 279
Epitomics approach for ovarian cancer biomarkers in serum 280
Gene expression studies in ovarian cancer 281
HE4 protein in urine as a biomarker for ovarian cancer 281
HtrA1 as a biomarker of response to chemotherapy in ovarian cancer 281
Mutation of genes in ovarian cancer 282
Serum biomarkers of ovarian cancer prognosis 282
Serum albumin-associated peptides and proteins 282
Multiplex assays for biomarkers of ovarian cancer 283
Concluding remarks on biomarker-based tests of ovarian cancer 284
Pancreatic cancer biomarkers 284
Discovery and validation of pancreatic cancer biomarkers 285
Cancer stem cells as biomarkers of pancreatic cancer 285
Histone modifications used as biomarkers in pancreatic cancer 285
miRNA biomarkers of pancreatic cancer 286
Parathyroid cancer biomarkers 287
Proteomic biomarkers of pancreatic cancer 287
Prostate cancer 288
Adipose tissue-derived biomarkers of obesity-related prostate cancer 289
B7-H3 as biomarker of prostate cancer 289
Cancer genetics-guided biomarker signatures of prostate cancer 289
Detection of prostate cancer biomarkers in urine 290
Detection of prostatic intraepithelial neoplasia 291
Epigenetic biomarkers of prostate cancer 291
Gene expression analysis of prostate cancer 291
Genetic biomarkers of prostate cancer 292
Huntingtin Interacting Protein 1 overexpression in prostate cancer 292
Id proteins expression in prostate cancer 293
Identification of prostate cancer mRNA biomarkers 293
Integrative genomic and proteomic profiling of prostate cancer 293
LCM for diagnosis of prostate cancer 293
Loss of p27 as predictor of recurrence of prostate cancer 294
Microarray for diagnosis of prostate cancer 294
miRNA biomarkers of prostate cancer 294
Prostate cancer biomarkers in semen 295
PSA as biomarker of prostate cancer 295
ProPSA as biomarker of prostate cancer 296
Prostate Health Index 296
Prostasomes in blood as biomarker of prostate cancer 296
PSMA as biomarker of prostate cancer 296
Sarcosine as a metabolic biomarker of prostate cancer 297
Serum HAAH as biomarker of prostate cancer 297
Silenced CDH13 gene as a biomarker of cancer 297
Serum-protein fingerprinting 297
Tests for prostate cancer based on genetic dislocations 298
Concluding remarks on biomarkers of prostate cancer 298
Renal cancer biomarkers 298
Gene expression profile of RCC for biomarkers 299
miRNA biomarkers of renal cancer 299
Use of proteomics for detection of RCC biomarkers 299
Use of RCC biomarkers for prognosis and therapy 300
Thyroid cancer biomarkers 300
Detection of BRAF mutation 301
Gene expression biomarkers of thyroid cancer 301
Multiple endocrine neoplasia type 2B as risk factor for thyroid cancer 301
miRNA biomarkers of thyroid cancer 302
Biochemical biomarkers of thyroid cancer 302
Role of the NCI in molecular diagnosis of cancer 302
The Cancer Genome Anatomy Project 302
Molecular profiling of cancer 303
Cancer Genome Atlas 303
Cancer Genetic Markers of Susceptibility Project 304
Oncology Biomarker Qualification Initiative 304
Role of NCI in cancer biomarker development and validation 304
Projects for cancer biomarker research in Europe 306
COBRED project 306
COLTHERES consortium 306
PREDICT Consortium 306
Future prospects for cancer biomarkers 307
Cancer biomarker research at academic institutions 307
Future prospects and challenges in the discovery of cancer biomarkers 307
7. Biomarkers of Disorders of the Nervous Syst