Biomarkers

Technologies, Markets and Companies

Publication Date	October 2009
Publisher	Jain PharmaBiotech
Product Type	Report
Pages	768
ISBN Number	not applicable
Product Code	JAI00026

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Summary

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 2008 to 2018 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 267 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 480 collaborations between companies and additional academic collaborations are mentioned in the individual profiles of companies. The report is supplemented by 800 references, 60 tables and 12 figures

Content

0 Executive Summary
1 Introduction
- Definitions
- Historical aspects of biomarkers
- Classification of biomarkers
  - Biological marker as response to therapeutic intervention
  - Pharmacokinetic/pharmacodynamics biomarkers
  - Predictive biomarkers
  - Valid biomarkers
- Types of biomarkers
  - Genes as biomarkers
  - Proteins as biomarkers
    - Proteomics
  - DNA biomarkers
  - Mitochondrial DNA
    - Mitochondrial mutations
  - RNA biomarkers
    - Transcriptomics
    - MicroRNAs
  - Metabolomics
  - Glycomics
  - Single nucleotide polymorphisms
    - Haplotyping
  - Cell biomarkers of disease
  - Stem cell biomarkers
    - Association of stem cell biomarkers with disease
    - Cancer stem cell biomarkers
    - Endoglin as a functional biomarker of stem cells
    - p75NTR as a biomarker to isolate adipose tissue-derived stem cells
    - Protein expression profile as biomarker of stem cells
    - STEMPRO ® EZChek™ for analysis of biomarkers of hESCs
    - SSEA-4 as biomarker of MSCs
  - Autoantibodies as biomarkers of autoimmune diseases
- Biomarkers and systems biology
  - Systems biology approach to biomarker identification
- Relation of biomarkers to other technologies and healthcare
  - Biomarkers and translational medicine
  - Limitations of use of biomarkers in healthcare
2 Technologies for Discovery of Biomarkers
- Introduction
  - The ideal biomarker
- Genomic technologies
  - Gene expression
    - Whole genome expression array
    - Gene expression profiling on whole blood samples
    - Profiling gene expression patterns of white blood cells
  - Tissue microarrays for study of biomarkers
- Epigenomic technologies
  - Discovery of methylation biomarkers
- Proteomic technologies
  - 2D GE
  - Isotope-coded affinity tags
  - Mass spectrometry
    - MALDI mass spectrometry for biomarker discovery
    - 2D PAGE and mass spectrometry
    - Quantitative tandem MS
    - Single-molecule mass spectrometry using a nanopore
    - Imaging mass spectrometry
    - Requirements for MS-based proteomic biomarker development
  - Liquid chromatography-MS/MS
  - Biomarker Amplification Filter
  - Protein tomography
  - Protein biochips/microarrays and biomarkers
    - Detection of biomarkers using peptide array technology
    - Protein nanobiochip
    - Antibody-based biomarker discovery
  - Real-time PCR for quantification of protein biomarkers
  - Magnetics beads for protein biomarker discovery
  - CellCarta® proteomics platform
  - MASStermind™
  - Search for biomarkers in body fluids
  - Challenges and strategies for discovey of protein biomarkers in plasma
    - 3-D structure of CD38 as a biomarker
    - BD™ Free Flow Electrophoresis System
    - Isotope tags for relative and absolute quantification
    - Plasma protein microparticles as biomarkers
    - Proteome partitioning
    - Stable isotope tagging methods
    - Technology to measure both the identity and size of the biomarker
  - Biomarkers in the urinary proteome
  - Peptides in body fluids and tissues as biomarkers of disease
    - Analysis of peptides in bodily fluids
    - Serum peptidome patterns
    - SISCAPA method for quantitating proteins and peptides in plasma
  - Comparison of proteomic profiling technologies for discovery of biomarkers
  - Verification for interlaboratory reproducibility of protein biomarkers
  - Significance of similar protein biomarkers in different tissues
- Glycomic technologies
- Metabolomic technologies
  - Mass spectrometry-based kits for discovery of metabolic biomarkers in plasma
  - Urinary profiling by capillary electrophoresis
  - Lipid profiling
  - Role of metabolomics in biomarker identification and pattern recognition
  - Validation of biomarkers in large-scale human metabolomics studies
- Lipidomics
- Disease biomarkers in breath
  - Portable breath test for volatile organic compounds
  - Detection of breath biomarkers by sensation technology
  - Detection of breath biomarkers optical frequency comb spectroscopy
- Fluorescent indicators for biomarkers
- Molecular imaging technologies
  - Computer tomography
  - Magnetic resonance imaging
  - Positron emission tomography
  - Advantages of imaging biomarkers
  - Monitoring in vivo gene expression by molecular imaging
  - Molecular imaging in vivo as a biomarker
  - Challenges and future prospects of molecular imaging
    - Basic research in molecular imaging
    - Imaging intracellular NADH as a biomarker of disease
    - Devices for molecular imaging
    - Imaging biomarkers in clinical trials
    - Molecular imaging in clinical practice
- Nuclear magnetic resonance
  - Chemical derivatization to enhance biomarker detection by NMR
  - Fluxomics by using NMR
- Nanobiotechnology
  - Nanomaterials for biolabeling
    - Quantum dot molecular labels
    - Bioconjugated QDs for multiplexed profiling of biomarkers
    - Magnetic nanotags for multipley detection of biomarkers
  - Nanoproteomics and biomarkers
    - High-field asymmetric waveform ion mobility mass spectrometry
  - Nanoparticles for molecular imaging
  - Nanoparticles for discovering biomarkers
  - Nucleoprotein nanodevices for detection of cancer biomarkers
  - Future prospects of application of nanobiotechnology for biomarkers
- Bioinformatics
  - Biomarker Workflow Guide
  - Analysis of microarray data for selecting useful biomarkers
  - Role of bioinformatics in discovery of proteomic biomarkers
  - Role of bioinformatics in detection of cancer biomarkers
  - Biomarker databases
  - Gene networks as biomarkers
3 Biomarkers and Molecular Diagnostics
- Introduction
- Molecular diagnostic technologies
  - Polymerase chain reaction
    - Amplification
    - Target selection
    - Detection of amplified DNA
    - Limitations of PCR
  - Real-time PCR systems
    - Limitations of real-time PCR
    - Future applications of real-time Q-PCR
  - Combined PCR-ELISA
  - Non-PCR methods
    - Linked Linear Amplification
  - Transcription mediated amplification
  - Rapid analysis of gene expression
  - WAVE nucleic acid fragment analysis system
  - DNA probes with conjugated minor groove binder
  - Rolling circle amplification technology
    - Gene-based diagnostics through RCAT
    - RCAT-immunodiagnostics
    - RCAT-biochips
    - RCAT-pharmacogenomics
  - Circle-to-circle amplification
  - Biochips and microarrays
    - Applications of biochips/microarrays
    - Role of biochip/microarrays in discovery of biomarkers
- Biomarkers and high throughput molecular screening
- Detection and expression profiling of miRNA
  - Real-time PCR for expression profiling of miRNAs
  - Real-time PCR for expression profiling of miRNAs
  - Use of LNA to explore miRNA
  - Microarrays for analysis of miRNA gene expression
4 Biomarkers for Drug Discovery & Development
- Introduction
- Biomarker technologies for drug discovery
  - Proteomics-based biomarkers for drug discovery
  - Chemoproteomics
  - Transcriptomics for drug discovery
  - Metabolomics for drug discovery
- Biomarkers and drug safety
  - Biomarkers of adverse drug reactions
  - Applications of biomarkers in drug safety studies
  - Genomic technologies for toxicology biomarkers
  - Proteomic technologies for toxicology biomarkers
  - Metabonomic technologies for toxicology biomarkers
  - Integration of genomic and metabonomic data to develop toxicity biomarkers
  - Toxicology studies based on biomarkers
    - Biomarkers of hepatotoxicity
    - Biomarkers of nephrotoxicity
    - Cardiotoxicity
    - Neurotoxicity
- Applications of biomarkers for drug development
  - Application of metabonomics/metabolomics for drug development
  - Role of pharmacokinetic/pharmacodynamic biomarkers in drug development
  - Molecular imaging as a biomarker in drug development
    - Molecular imaging in preclinical studies
    - Molecular imaging in clinical trials
    - Prospects of molecular imaging in drug discovery and development
  - Biomarkers in clinical trials
    - NIH recommendations on the use of biomarkers in clinical trials
    - Advantages of biomarkers for drug development
    - Limitations and problems with use of biomarkers in clinical trials
  - Application of biomarkers by the pharmaceutical companies
  - Use of biomarkers in relation to stage of drug discovery and development
  - Drug development in cardiovascular disorders
  - Drug development in neurological disorders
  - Future prospects of biomarker-based drug development
    - The Biomarker Alliance
    - Molecular Libraries and Imaging Roadmap of NIH
    - Biomarkers Consortium
5 Role of Biomarkers in Healthcare
- Introduction
- Biomarkers of inflammation
- Biomarkers of oxidative stress
  - Oxidative DNA damage
  - Proteins as biomarkers of oxidative stress in diseases
  - 1,4-dihydroxynonane-mercapturic acid
- Biomarkers in metabolic disorders
  - Biomarkers of acute intermittent porphyria
  - Liver X receptors
  - Biomarkers of diabetes mellitus
    - Biomarkers of hyperglycemia
    - Biomarkers of diabetes-associated oxidative stress
    - Biomarkers of inflammation associated with diabetes
    - Biomarkers of renal complications in diabetes mellitus type 2
    - Biomarkers of diabesity
    - Glycosylated hemoglobin in diabetes mellitus
    - Lack of C-peptide as biomarker of complications of diabetes type 1
    - Serum retinol binding protein 4 as biomarker of insulin resistance
  - Biomarkers of metabolic syndrome
    - Adiponectin
- Biomarkers in immune disorders
  - Biomarkers of failure of transplanted organs
    - Immunological biomarkers of graft versus host disease
    - Biomarkers of renal allograft failure
    - Biomarkers of lung transplant rejection
  - Systemic lupus erythematosus
    - Current management and need for biomarkers
    - Role of collaborative efforts and databases of SLE biomarkers
    - C4d-bearing reticulocytes
    - Adiponectin
    - CB-CAPS
    - Genetic loci of SLE
    - Epigenetic biomarkers of SLE
- Biomarkers of musculoskeletal disorders
  - Biomarkers of rheumatoid arthritis
  - Biomarkers of spondylarthritis
  - Biomarkers of osteoarthritis
- Biomarkers of osteoporosis
  - Dual x-ray absorptiometry
  - Bone imaging with quantitative CT and MRI
  - Assays for detection of biomarkers of osteoporosis
- Biomarkers of infectious diseases
  - Application of proteomics for discovering biomarkers of infections
  - Systemic inflammatory response syndrome
  - Tuberculosis
    - Conventional diagnosis of tuberculosis
    - Molecular diagnostics for tuberculosis
    - Biomarkers for tuberculosis
    - Biomarkers of pulmonary tuberculosis in the breath
  - Biomarkers of viral infections
    - Viral hepatitis
    - Biomarkers of SARS
    - Biomarkers of HIV
  - Biomarkers in parasitic infections
    - Role of biomarkers in malaria
    - Identification of biomarkers in Schistosomiasis infections
- Biomarkers of liver disease
  - Breath biomarkers of liver disease
  - Biomarkers of viral hepatitis B and C
  - Biomarkers of liver injury
  - Biomarkers of liver cirrhosis
  - FibroMax
- Biomarkers of pancreatitis
- Biomarkers of renal disease
  - Cystatin C as biomarker of glomerular filtration rate
  - Proteomic biomarkers of acute kidney injury
  - Biomarkers of lupus nephritis
  - Biomarkers of diabetic nephropathy
- Biomarkers of pulmonary diseases
  - Biomarkers of oxidative stress in lung diseases
  - Biomarkers of survival in acute respiratory distress syndrome
    - Urinary NO as biomarker
    - Plasma biomarkers related to inflammation
  - Pulmonary surfactant proteins as biomarkers for lung diseases
    - Cytokine/chemokine biomarkers of SARS
  - Biomarkers of chronic obstructive pulmonary disease
    - Increased expression of PIGF as a biomarker of COPD
    - Chromagranin A (CgA) as biomarker of airway obstruction in smokers
    - BNP as a biomarker of chronic pulmonary disease
    - Alpha1-antitrypsin gene polymorphisms predisposing to emphysema
  - Biomarkers of asthma
    - Comparison of biomarkers of asthma and COPD
    - Exaled NO as a biomarker of asthma
    - Cytokines as biomarkers of asthma severity
    - Biomarker for rhinovirus-induced asthma exacerbation
    - Biomarkers for predicting response to corticosteroid therapy
    - IgE as guide to dosing of omalizumab for asthma
    - Endothelin-1 in exhaled breath as biomarker of asthma
  - Biomarkers for cystic fibrosis
  - Biomarkers of pulmonary embolism
- Biomarkers in obstetrics and gynecology
  - Biomarkers for preeclampsia
    - Protein biomarker of preeclampsia in urine
    - Protein biomarkers of preeclampsia in CSF
    - Protein HtrA1 as biomarker for preeclampsia
    - sFlt1 and soluble endoglin as biomarkers of preeclampsia
    - RNA biomarkers
  - Biomarkers of premature birth
  - Biomarkers of oxidative stress in complicated pregnancies
  - Biomarkers of premenstrual dysphoric disorder
  - Biomarkers of endometriosis
  - Fetal biomarkers in maternal blood
- Biomarkers for genetic disorders
  - Biomarkers for Down's syndrome
  - Biomarkers for muscular dystrophy
  - Biomarkers of phenylketonuria
  - Genetic biomarkers for psoriasis
  - Biomarkers of lysosomal storage disorders
- Biomarkers of aging
  - Study of biomarkers of aging in a genetically homogeneous population
  - Genes as biomarkers of aging
    - Telomere attrition as aging biomarker
    - Mitochondrial mutations as biomarkers of aging
  - Role of bioinformatics in search for biomarkers of aging
  - Effect of calorie restriction on biomarkers of longevity
- Biomarkers of miscellaneous disorders
  - Biomarkers of inflammatory bowel disease
  - Biomarkers of erectile dysfunction
  - Biomarkers of heat stroke
  - Biomarkers of pain
    - Biomarkers of neuropathic pain
    - Brain insular glutamate as biomarker of fibromyalgia
    - Biomarkers of visceral pain
  - Nasal nitric oxide as a biomarker of response to rhinosinusitis therapy
  - Biomarkers common to multiple diseases
- Biomarkers and nutrition
  - Biomarkers in nutritional epidemiology
  - Biomarkers of nutritional status
  - Biomarkers of branched chain amino acid status
  - Biomarkers of caloric restriction
  - Biomarkers of malnutrition
  - Proteomic biomarkers and nutrition
- Biomarkers of gene-environmental interactions in human disease
6 Biomarkers of Cancer
- Introduction
  - The ideal biomarker for cancer
  - Single vs multiple biomarkers of cancer
- Types of cancer biomarkers
  - miRNAs as biomarkers in cancer
    - Circulating miRNAs for cancer detection
    - Diagnostic value of miRNA in cancer
  - Biomarkers of epigenetic gene silencing in cancer
  - Immunologic biomarkers of cancer
- Molecular diagnostic techniques for cancer
- Technologies for detection of cancer biomarkers
  - Genomic technologies for cancer biomarkers
    - Cold-PCR
    - Genome analysis at the molecular level
    - Sequencing-based approaches for detection of cancer biomarkers
    - Early detection of tumor suppressor gene mutations
    - Biomarkers of PTEN tumor suppressor gene status
    - HAAH as a biomarker for cancer
    - Telomerase as a biomarker of cancer
    - Digital karyotyping for cancer biomarkers
    - LigAmp for detection of gene mutations in cancer
    - Mitochondrial DNA as a cancer biomarker
  - Tissue microarrays for study of cancer biomarkers
  - Molecular fingerprinting of cancer
  - Biomarkers of inflammation in cancer
  - Proteomic technologies for detecting biomarkers of cancer
    - 2D PAGE
    - Antibody-based detection of protein biomarkers
    - Aptamer-based molecular probes for cancer biomarker discovery
    - Cancer immunomics to identify autoantibody signatures
    - Desorption electrospray ionization for detection of cancer biomarkers
    - Detection of circulating nucleosomes in serum of cancer patients
    - Detection of tumor markers with ProteinChip technology
    - eTag assay system for cancer biomarkers
    - Glycoprotein biomarkers of cancer
    - HER-2/neu oncoprotein as biomarkers for cancer
    - Humoral proteomics
    - Laser capture microdissection
    - Phage display technology
    - Proteomic analysis of cancer cell mitochondria
    - Proteomic technologies for detection of autoimmune biomarkers
    - SELDI-TOF MS
    - Serum proteome analysis for early detection of cancer
    - Tissue proteomics for discovery of cancer biomarkers
  - Metabolomic biomarkers of cancer
    - Choline phospholipid biomarkers of cancer
    - Hypoxia-inducible factor-1
    - Detection of drug resistance in cancer by metabolic profiling
  - Epitomics for the early detection of cancer
  - Detection of biomarkers of DNA methylation
    - PCR with bisulfite for detecting DNA methylation biomarkers in cancer
    - MDScan™ microarray technology
    - Rubicon MethylPlex technology
    - Epigenomics Marker Machine for DNA methylation biomarkers
    - Sequenom's integrated genetic analysis platform
    - Histone deacetylase
    - Mucins as epigenetic biomarkers in epithelial cancers
  - Nanobiotechnology for early detection of cancer to improve treatment
  - Selective expression of biomarkers by cancer compared with normal tissues
  - Ultrasound radiation to enhance release of a tumor biomarker
  - In vivo imaging of cancer biomarkers
    - Computer tomography
    - Optical systems for in vivo molecular imaging of cancer
    - Positron emission tomography
    - Imaging of tumor oxygenation and microvascular permeability by MRI
    - Xenon-enhanced MRI
  - Kallikrein gene family and cancer biomarkers
  - Circulating cancer cells in blood as biomarkers of cancer
- Applications of cancer biomarkers
  - Use of biomarkers for cancer classification
    - Cancer classification using microarrays
    - Proteomic classification of cancer
  - Use of biomarkers for early detection of cancer
  - Applications of biomarkers for cancer diagnosis
    - Methylated DNA sequences as cancer biomarkers
    - MicroRNA expression profiling for diagnosis of human cancers
    - MUC4 as a diagnostic biomarker in cancer
  - Applications of biomarkers for cancer diagnosis and therapy
    - Asparagine synthetase as biomarker for therapy with L-asparaginase
    - Peptide-based agents for targeting cancer biomarkers
  - Biomarkers for assessing efficacy of cancer therapy
    - ERCC1-XPF expression as a biomarker of response to chemotherapy
    - GRP78 as a predictor for chemoresponsiveness of breast cancer
    - HtrA1 as a biomarker of response to chemotherapy in ovarian cancer
    - P53 expression level as biomarker of efficacy of cancer gene therapy
  - Biomarkers of angiogenesis for developing antiangiogenic therapy
    - Tumor endothelial markers
    - Circulating endothelial cells as targets for antiangiogenic drugs
    - Biomarkers of response to antiangiogenic agent brivanib alaninate
    - DCE-MRI biomarkers for evaluation of antiangiogenic agents
    - Combination of soluble biomarkers of angiogenesis with imaging
  - Biomarkers of drug resistance in cancer
    - A systems approach to biomarkers of innate drug resistance
    - Epithelial membrane protein-1 as a biomarker of gefitinib resistance
    - Methylation biomarkers of drug resistance in cancer
  - Biomarkers of radiation exposure
- Role of biomarkers in drug development in oncology
  - Molecular imaging of tumor as a guide to drug development
    - Use of PET to assess response to anticancer drugs
    - Use of MRI to assess response to anticancer drugs
  - Biomarkers in plucked hair for assessing cancer therapy
  - Molecular targets of anticancer drugs as biomarkers
  - Safety biomarkers in oncology studies
  - Role of biomarkers in phase I clinical trials of anticancer drugs
- Biomarkers according to location/type of cancer
  - Bladder cancer biomarkers
    - Urinary telomerase as biomarker for detection of bladder cancer
  - Brain cancer biomarkers
    - Biomarkers to predict response to EGFR inhibitors
    - CD133 as biomarker of resistance to radiotherapy
    - Circulating microvesicles as biomarkers
    - CSF protein profiling
    - CSF attractin as a biomarker of malignant astrocytoma
    - Methylation profiling of brain tumors
    - Metabolite biomarkers of brain tumors
    - miRNA biomarker of brain tumors
    - MRI biomarker for response of brain tumor to therapy
    - Neuroimaging biomarkers combined with DNA microarray analysis
    - Receptor protein tyrosine phosphatase ß as biomarker of gliomas
    - Serum protein fingerprinting
  - Breast cancer biomarkers
    - Biomarkers of breast cancer in breath
    - Biomarkers for breast cancer in nipple aspiration fluid
    - Decreased breast density as a biomarker of response to tamoxifen
    - Flow cytometry for quantification of biomarker expression patterns
    - Plasma proteomics for biomarkers of breast cancer
    - Quantitative realtime PCR assays for biomarker validation
    - Cdk6 as a biomarker of breast cancer
    - Centromere protein-F
    - Carbonic anhydrase IX
    - COX-2 as a biomarker of breast cancer
    - Glycomic biomarkers of breast cancer
    - HER-2/neu oncoprotein
    - High mobility group protein A2
    - Lipocalin 2 as biomarker of breast cancer progression
    - Mammaglobin
    - p27 expression as biomarker for survival after chemotherapy
    - Podocalyxin
    - Progranulin as a biomarker of breast cancer
    - Proliferating cell nuclear antigen
    - Protein kinase C as a predictive biomarker of metastatic breast cancer
    - Retinoblastoma tumor suppressor gene as a biomarker
    - Riboflavin carrier protein
    - Serum CA 15-3 as biomarker of prognosis in advanced breast cancer
    - Suppressor of deltex protein
    - Tumor microenvironment as biomarker of metastasis in breast cancer
    - Type III TGF-ß receptor as regulator of cancer progression
    - Diagnostic tests based on breast cancer genes
    - Prognostic role of breast cancer genes
    - Protein biomarkers for breast cancer prevention
    - Biomarkers to evaluate efficacy of chemoprevention
    - Biomarker prognosis of breast cancer treated with doxorubicin
  - Cervical cancer biomarkers
  - Gastrointestinal cancer biomarkers
    - Gastric cancer biomarkers
    - Colorectal cancer biomarkers
  - Head and neck cancer
  - Leukemia biomarkers
    - Chromosome translocations in leukemias
    - DNA methylation biomarkers in leukemia
    - Gene mutations as biomarkers in leukemia
    - Molecular diagnostic techniques for leukemia
    - Proteomic technologies for discovering biomarkers of leukemia
    - Biomarkers of chronic lymphocytic leukemia
    - Biomarkers of chronic myeloid leukemia
    - Biomarkers of drug resistance in leukemia
    - Biomarkers of myelodysplasitic syndromes
  - Liver cancer biomarkers
  - Lung cancer biomarkers
    - Autoantibodies as biomarkers in lung cancer
    - Biomarkers associated with neuroendocrine differentiation in NSCLC
    - Biomarkers of chronic inflammation in lung cancer
    - Biomarkers for predicting sensitivity to chemotherapy in lung cancer
    - Biomarkers for prediction of sensitivity to EGFR inhibitors
    - Circulating tumor cells as biomarkers
    - Gene expression profiling for biomarkers of lung cancer
    - Methylation biomarkers of lung cancer
    - miRNA biomarkers in lung cancer
    - Proteomic biomarkers in exaled breath condensate
    - Serum protein biomarkers of lung cancer
    - tNOX as biomarker of lung cancer
    - Tumor-derived DNA and RNA markers in blood
    - Volatile organic compounds in the exhaled breath
  - Malignant pleural mesothelioma
  - Melanoma biomarkers
  - Nasopharyngeal carcinoma biomarkers
    - Proteomic biomarkers of nasopharyngeal cancer
    - miRNA biomarkers of nasopharyngeal carcinoma
  - Oral cancer biomarkers
  - Ovarian cancer biomarkers
    - Gene exprression studies
    - Mutation of genes
    - Serum CA-125 as biomarker of ovarian cancer prognosis
    - Serum albumin-associated peptides and proteins
    - Multiplex assays for biomarkers of ovarian cancer
    - Epitomics approach for ovarian cancer biomarkers in serum
    - Concluding remarks on biomarker-based tests of ovarian cancer
  - Pancreatic cancer biomarkers
    - Discovery and validation of pancreatic cancer biomarkers
    - Cancer stem cells as biomarkers of pancreatic cancer
    - miRNA biomarkers of pancreatic cancer
    - Proteomic biomarkers of pancreatic cancer
  - Prostate cancer
    - Adipose tissue-derived biomarkers of obesity-related prostate cancer
    - B7-H3 as biomarker of prostate cancer
    - Detection of prostate cancer biomarkers in urine
    - Detection of prostatic intraepithelial neoplasia
    - Epigenetic biomarkers of prostate cancer
    - Genetic biomarkers of prostate cancer
    - Huntingtin Interacting Protein 1 overexpression in prostate cancer
    - Id proteins expression in prostate cancer
    - Identification of prostate cancer mRNA biomarkers
    - Integrative genomic and proteomic profiling of prostate cancer
    - LCM for diagnosis of prostate cancer
    - Loss of p27 as predictor of recurrence of prostate cancer
    - Microarray for diagnosis of prostate cancer
    - miRNA biomarkers of prostate cancer
    - Prostate cancer biomarkers in semen
    - PSA as biomarker of prostate cancer
    - PSMA as biomarker of prostate cancer
    - Serum HAAH as biomarker of prostate cancer
    - Silenced CDH13 gene as a biomarker of cancer
    - Serum-protein fingerprinting
    - Tests for prostate cancer based on genetic dislocations
    - Concluding remarks on biomarkers of prostate cancer
  - Renal cancer biomarkers
    - Gene expression profile of RCC for biomarkers
    - miRNA biomarkers of renal cancer
    - Use of proteomics for detection of RCC biomarkers
    - Use of RCC biomarkers for prognosis and therapy
  - Thyroid cancer biomarkers
    - Gene expression biomarkers of thyroid cancer
    - Multiple endocrine neoplasia type 2B as risk factor for thyroid cancer
    - miRNA biomarkers of thyroid cancer
    - Biochemical biomarkers of thyroid cancer
- Role of the NCI in molecular diagnosis of cancer
  - The Cancer Genome Anatomy Project
  - Molecular profiling of cancer
  - Cancer Genome Atlas
  - Cancer Genetic Markers of Susceptibility Project
  - Oncology Biomarker Qualification Initiative
  - Role of NCI in cancer biomarker development and validation
- COBRED project for cancer biomarker research in Europe
- Future prospects for cancer biomarkers
  - Cancer biomarker research at academic institutions
  - Future prospects and challenges in the discovery of cancer biomarkers
7 Biomarkers of Disorders of the Nervous System
- Introduction
- Discovery of biomarkers for neurological disorders
  - Biomarker identification in the CSF using proteomics
  - Biomarker identification in the CSF using lipidomics
  - Cerebral microdialysis for the study of biomarkers of cerebral metabolism
  - Detection of protein biomarkers of CNS disorders in the blood
  - Brain imaging for detection of biomarkers
- Data mining for biomarkers of neurological disorders
- Antibodies as biomarkers in disorders of the nervous system
- Biomarkers of neural regeneration
- Biomarkers of disruption of blood-brain barrier
- Biomarkers of neurotoxicity
  - Glial fibrillary acidic protein as biomarker of neurotoxicity
  - Single-stranded DNA as a biomarker of neuronal apoptosis
- Biomarkers of neurodegenerative disorders
  - Biomarkers of Alzheimer's disease
    - The ideal biomarker for AD
    - Protein biomarkers of AD in CSF
    - Amyloid precursor protein
    - Tau proteins in CSF
    - Tests for the detection of Aß in CSF
    - Monitoring of synthesis and clearance rates of Aß in the CSF
    - Tests combining CSF tau and Aß
    - CSF sulfatide as a biomarker for AD
    - Glycerophosphocholine as CSF biomarker in AD
    - CSF Reelin as biomarker of AD
    - Urine tests for AD
    - Blood tests for AD
    - Protein kinase C in red blood cells
    - Detection of aggregated misfolded proteins in the blood
    - Lymphocyte Proliferation Test
    - A biomarker-based skin test for AD
    - Radioiodinated clioquinol as a biomarker for Aß
    - Nanotechnology to measure Aß
    - -derived diffusible ligands
    - Simultaneous measurement of several biomarkers for AD
    - Use of biomarkers to predict AD in patients with MCI
    - Genetic tests for AD
    - Gene expression patterns in AD
    - Magnetic resonance spectroscopy in AD
    - MRI for biomarkers of AD
    - PET scanning for biomarkers of AD
    - Targeting of chemokine receptor as biomarker for brain imaging
    - Plasma biomarkers of drug response in AD
    - Concluding remarks about biomarkers for AD
  - Biomarkers of Parkinson's disease
    - Biochemical biomarkers of PD
    - Biomarkers of PD based on gene expression in blood
    - Cardiac denervation as a biomarker of PD
    - Imaging biomarkers of PD
    - Metabolic brain networks as biomarkers
    - Metabonomic biomarker profile for diagnosis and monitoring of PD
    - Future prospects for biomarkers of PD
  - Biomarkers of Huntington's disease
    - Quantitative MRI measurement of brain atrophy as biomarker of HD
  - Biomarkers of Wilson's disease
  - Biomarkers of amyotrophic lateral sclerosis
    - Biomarkers of neuroinflammation in ALS
    - Detection of ALS biomarkers in blood vs CSF
    - Ideal biomarker of ALS
    - Imaging biomarkers of ALS
    - Metabolomic biomarkers of ALS
    - Proteomic biomarkers of ALS
    - Future prospects of biomarkers of ALS
  - Biomarkers of dementia in HIV-1-infected patients
  - Biomarkers of prion diseases
    - 14-3-3 protein and tTau/P-Tau ratio
    - Bioluminescence imaging as a surrogate biomarker of prion infectivity
- Biomarkers of multiple sclerosis
  - Antibodies in multiple sclerosis
    - Antibodies to galactocerebroside
    - Antibodies to myelin oligodendrocyte glycoprotein
    - Detecting autoantibodies in multiple sclerosis
  - CSF Cystatin C as a biomarker of multiple sclerosis
  - T cells as biomarkers of multiple sclerosis
  - Matrix metalloproteinases as biomarkers in multiple sclerosis
  - Gelsolin as a biomarker of multiple sclerosis
  - Gene expression profiling of biomarkers in multiple sclerosis
  - Serum proteomic pattern analysis in multiple sclerosis
  - Biomarkers of remyelination and repair
    - Myelin imaging by PET
  - Biomarkers of response to therapy of multiple sclerosis
  - Concluding remarks and future perspective for biomarkers of multiple sclerosis
- Biomarkers of stroke
  - Biomarkers of intracerebral hemorrhage
  - Biomarkers of hypoxic brain damage
  - Brain natriuretic peptide as a biomarker for cardioembolic stroke
  - Brain lactate and N-acetylaspartate as biomarkers of stroke
  - Intercellular adhesion molecule 1 as biomarker of ischemic stroke
  - Lp-PLA2 and CRP as biomarkers for stroke
  - Neuroserpin polymorphisms as a biomarker of stroke
  - NMDA receptors as biomarkers of excitotoxicity in stroke
  - Nucleosomes as biomarkers of stroke
  - PARK7 and nucleoside diphosphate kinase A as biomarkers of stroke
  - Visinen-like protein 1
  - Gene expression in blood following ischemic stroke
  - Future prospects for biomarkers of stroke
- Biomarkers of traumatic brain injury
  - Technologies for identification of biomarkers of TBI
    - Proteomic technologies for biomarkers of TBI
    - Cerebral microdialysis for study of biomarkers of TBI
  - Biomarkers of TBI
    - C-tau as biomarker of TBI
    - Hyperphosphorylated axonal neurofilament protein
    - IL-6 and nerve growth factor as biomarkers of TBI
    - Serum S100B as biomarker of TBI
  - Biomarkers of inflicted TBI in infants
  - Clinical applications of biomarkers of TBI
- Biomarkers of CNS infections
  - Biomarkers of CNS HIV infection
  - Biomarkers of bacterial meningitis
- Biomarkers of epilepsy
  - Genetic epilepsies
  - Biochemical markers of epilepsy
  - Imaging biomarkers of epilepsy
- Biomarkers of normal pressure hydrocephalus
- Biomarkers of retinal disorders
  - Biomarkers of age-related macular degeneration
- Biomarkers for autism
- Biomarkers of sleep disorders
  - Biomarker of excessive daytime sleepiness
  - Biomarkers of obstructive sleep apnea
  - Biomarkers of restless legs syndrome
- Biomarkers of psychiatric disorders
  - Biomarkers of depression
  - Biomarkers of psychosis
  - Biomarkers of schizophrenia
    - Genetic biomarkers of schizophrenia
    - Gene expression analysis of blood for biomarkers of schizophrenia
    - Proteomic studies for biomarkers of schizophrenia
    - Metabolic biomarkers of schizophrenia
8 Biomarkers of Cardiovascular Disorders
- Introduction
  - Epidemiology of cardiovascular disease
- Biomarkers of cardiovascular diseases
  - Genetic biomarkers of cardiovascular disorders
- Methods for identification of cardiovascular biomarkers
  - Application of proteomics for biomarkers of cardiovascular disease
  - Detection of biomarkers of myocardial infarction in saliva by a nanobiochip
  - Metabolomic technologies for biomarkers of myocardial ischemia
  - Imaging biomarkers of cardiovascular disease
    - Cardiovascular MRI
    - Annexin A5 as an imaging biomarker of cardiovascular disease
- Applications of biomarkers of cardiovascular disease
  - Biomarkers for ischemic heart disease and myocardial infarction
    - Troponin
    - Natriuretic peptide
    - Creatine kinase muscle brain
    - Myoglobin
    - Fatty acid binding protein
    - Cripto-1 as a biomarker of myocardial infarction
    - Cataract as a biomarker of ischemic heart disease
    - Plasma fetuin-A levels and the risk of myocardial infarction
  - Biomarkers of congestive heart failure
    - Angiogenesis biomarkers
    - beta-2a protein as a biomarker of heart failure
    - Galectin-3 as biomarker of acute heart failure
    - G protein-coupled receptor kinase-2 as biomarker of CHF
    - KIF6 gene as biomarker of CHF
    - NT ProBNP as biomarker of CHF
    - Oxidative stress as biomarker of heart failure
    - Future prospects for biomarkers of heart failure
  - Biomarkers for atherosclerosis
    - Adipocyte enhancer-binding protein 1
    - Ghrelin as a biomarker of atherosclerosis
    - Imaging biomarkers of hypercholesterolemia/atherosclerosis
    - Inflammatory biomarkers of atherosclerosis
    - Lipid-modified proteins as biomarkers of atherosclerosis
    - Lp-PLA2 as biomarker of atherosclerotic heart disease
    - Nitric oxide impairment and atherosclerosis
    - Oxygen free radicals as biomarkers of atherosclerosis
    - Proteomic profiles of serum inflammatory markers of atherosclerosis
  - Biomarkers of risk factors for coronary heart disease
    - Antibody to oxidized-LDL
    - Apolipoproteins as risk factors for coronary heart disease
    - CRP as biomarker of risk for coronary heart disease
    - Impairment of EPCs by oxidative stress as a biomarker of disease
  - Biomarkers for pulmonary arterial hypertension
    - Biomarkers of abdominal aortic aneurysm
  - Genetic biomarkers for cardiovascular disease
    - Genetic biomarkers of atherosclerosis
    - IL-1 gene polymorphism as biomarker of cardiovascular disease
    - Polymorphisms of the eNOS gene and angina pectoris
    - Polymorphisms in the apolipoprotein E gene
    - Mutations in the low density lipoprotein receptor gene
    - Mutations within several genes that code for ion channel
    - Polymorphism in the angiotensinogen gene
    - Kallikrein gene mutations in cardiovascular disease
    - Kallikrein gene and essential hypertension
    - Gene mutations in pulmonary arterial hypertension
    - Genetic biomarkers of early onset myocardial infarction
    - Gene variant as a risk factor for sudden cardiac death
  - Multiple biomarkers for prediction of death from cardiovascular disease
- Role of biomarkers in the management of cardiovascular disease
  - Role of biomarkers in the diagnosis of myocardial infarction
  - Role of biomarkers in the prevention of cardiovascular disease
  - Molecular signature analysis in management of cardiovascular diseases
  - C-reactive protein as biomarker of response to statin therapy
  - Role of circulating biomarkers and mediators of cardiovascular dysfunction
  - Use of biomarkers in the management of peripheral arterial disease
  - Use of biomarkers in the management of hypertension
  - Use of protein biomarkers for monitoring acute coronary syndromes
  - Use of multiple biomarkers for monitoring of cardiovascular disease
- Future prospects for cardiovascular biomarkers
  - Cardiovascular Biomarker Consortium
  - Systems Approach to Biomarker Research in Cardiovascular Disease
9 Biomarkers & Personalized Medicine
- Introduction
- Pharmacogenetics
  - Biomarkers and pharmacogenetics
- Pharmacogenomics
- Pharmacoproteomics
  - Single cell proteomics for personalized medicine
- Role of biomarkers in development of personalized drugs
  - Use of biomarkers for developing MAb therapy in oncology
- Biobanking, biomarkers and personalized medicine in EU
- Expression signatures as diagnostic/prognostic tools
- Biomarkers for monitoring response to therapy
- Drug rescue by biomarker-based personalized medicine
- Future role of biomarkers in personalized medicine
10 Regulatory issues
- Introduction
- Biomarker validation
  - FDA criteria for a valid biomarker
  - Role of NIST in validation of cancer biomarkers
  - Quality specifications for BNP and NT-proBNP as cardiac biomarker assays
- FDA perspective of biomarkers in clinical trials
- FDA and predictive medicine
- Biomarkers and FDA's Voluntary Genomic Data Submission
- Role of imaging biomarkers in approval of drugs
- FDA Critical Path Initiative and biomarker R&D
  - FDA consortium linking genetic biomarkers to serious adverse events
  - Oncology Biomarker Qualification Initiative
  - Critical Path Initiative
    - Predictive Safety Testing Consortium
  - From validated biomarker assay to a clinical laboratory diagnostic
  - Fast Path programs
  - Need for a single federal agency to oversee biomarker field
11 Markets for Biomarkers
- Introduction
- Biomarker markets according to technologies/applications
  - Markets for protein biomarkers
  - Biomarker market relevant to drug discovery and development
  - Biomarker market relevant to epigenetics
  - Biomarket market relevant to bioinformatics
- Biomarker markets according to therapeutic areas
- Geographical distribution of biomarker markets
- Unfulfilled needs in biomarkers
- Drivers for the growth of markets for biomarkers
- Challenges facing the biomarker industry
  - Pitfalls in the discovery and development of biomarkers
- Strategies for developing biomarker markets
  - Utilization of biomarker research in academic laboratories
  - Biomarker discovery at pharmaceutical companies
  - Industrial-academic collaborations in biomarkers
  - Application of biomarkers in medical practice
    - Future role of biomarkers in healthcare
  - Applications of biomarkers beyond healthcare
    - Combating bioterrorism
    - Biomarkers for monitoring human exposure to environmental toxins
    - Application of biomarkers in animal health
- Biomarker patents
  - Factors that enhance the value of biomarker IP
  - US policy on gene patenting relevant to biomarkers
12 References
13 Companies
- Introduction
- Top companies in biomarkers
- Profiles of companies
- Collaborations
Tables
- Table 1-1: Historical landmarks in discovery and development of biomarkers
- Table 1-2: Classification of biomarkers
- Table 1-3: Terminology of biomarkers of disease relevant to clinical development
- Table 1-4: Autoimmune disorders under study for autoantibodies as predictors
- Table 1-5: Use of ""-omic"" technologies for discovery of biomarkers
- Table 1-6: Role of biomarkers in translational medicine
- Table 2-1: Classification of methods of gene expression analysis
- Table 2-2: Comparison of proteomic profiling technologies for discovery of biomarkers
- Table 2-3: Companies involved in developing molecular imaging
- Table 3-1: Applications of biochip/microarray technology in relation to biomarkers
- Table 4-1: Companies using metabolomics for drug discovery
- Table 4-2: Causes of failures in clinical trials and their reduction by use of biomarkers
- Table 4-3: Biomarker-based drug development at major pharmaceutical companies
- Table 5-1: Biomarkers of diabetes mellitus
- Table 5-2: Biomarkers of sepsis
- Table 5-3: Biomarkers of pulmonary diseases
- Table 5-4: Biomarkers of aging
- Table 5-5: Examples of biomarkers common to multiple diseases
- Table 6-1: Desirable characteristics of biomarkers for cancer
- Table 6-2: Types of cancer biomarkers
- Table 6-3: A classification of molecular diagnostic methods in cancer
- Table 6-4: Biomarkers of brain tumors
- Table 6-5: Biomarkers of breast cancer
- Table 6-6: Biomarkers of colorectal cancer
- Table 6-7: Biomarkers of lung cancer
- Table 6-8: Classification of biomarkers of melanoma
- Table 6-9: Biomarkers of nasopharyngeal carcinoma and potential applications
- Table 6-10: Biomarkers of ovarian cancer
- Table 6-11: Classification of biomarkers of pancreatic cancer
- Table 6-12: Biomarkers of prostate cancer
- Table 7-1: Biomarkers of cerebral metabolism
- Table 7-2: Classification of biochemical markers of AD in blood and CSF
- Table 7-3: Characteristics of an ideal biomarker for Alzheimer disease
- Table 7-4: Biomarkers of Parkinson's disease
- Table 7-5: Classification of biomarkers of sporadic amyotrophic lateral sclerosis
- Table 7-6: Biomarkers of multiple sclerosis
- Table 7-7: Biomarkers of response to interferon-ß in multiple sclerosis
- Table 7-8: Biomarkers of stroke
- Table 7-9: Biochemical biomarkers of traumatic brain injury
- Table 7-10: Biomarkers of epilepsy
- Table 8-1: Classification of biomarkers for cardiovascular diseases
- Table 8-2: Genes that cause cardiovascular diseases
- Table 9-1: Pharmacogenetic vs. pharmacogenomic studies
- Table 9-2: Applications of pharmacoproteomic biomarkers in personalized medicine
- Table 11-1: Biomarker markets according to technologies/applications 2008-2018
- Table 11-2: Biomarker markets according to therapeutic areas 2008-2018
- Table 11-3: Geographical distribution of biomarker markets 2008-2018
- Table 11-4: Factors driving the growth of biomarker industry
- Table 13-1: Companies with focus on biomarkers
- Table 13-2: Pharmaceutical and biotechnology companies involved in biomarkers
- Table 13-3: Molecular diagnostic companies
- Table 13-4: Proteomics metabolomic/metabonomic and systems biology companies
- Table 13-5: Pharmacogenomic/ personalized medicine companies
- Table 13-6: Companies with biochips, biosensors and imaging technologies
- Table 13-7: Nanobiotechnology companies
- Table 13-8: Companies involved in drug discovery and development
- Table 13-9: Bioinformatic companies involved in biomarkers
- Table 13-10: Service, equipment and reagent supply companies
- Table 13-11: Top biomarker companies
- Table 13-12: Collaborations between companies
Figures
- Figure 1-1: Relation of biomarkers to other technologies and healthcare
- Figure 2-1: The central role of spectrometry in proteomics
- Figure 4-1: Role of biomarkers in drug discovery and development process
- Figure 6-1: Role of proteomics in the discovery of cancer biomarkers
- Figure 6-2: Cancer biomarker development and validation
- Figure 7-1: Discovery and application of biomarkers in neurological diseases
- Figure 9-1: Role of pharmacogenetic biomarkers in personalized medicine
- Figure 9-2: Impact of biomarkers on personalized medicine
- Figure 10-1: Stages and timelines of biomarker discovery, development and marketing
- Figure 10-2: Biomarker qualification pilot process at the FDA
- Figure 10-3: From a validated biomarker assay to a clinical laboratory diagnostic
- Figure 11-1: Unfulfilled needs in biomarkers technologies and applications