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Biomarkers
Biomarkers, as defined by NIH, are "characteristics that are objectively
measured and evaluated as an indicator of normal biologic processes, pathogenic
processes, or pharmacologic responses to a therapeutic intervention." A
biomarker has to be reliable, measurable, specific, and predicative.
Understanding the multivariate nature of a disease and drug response depends on
molecular profiling at epigenetic, genetic, and protein levels. SABiosciences'
PCR Arrays, microRNA Arrays, Epigenetics ChIP Arrays, Methylation PCR Arrays,
and Biology-on-Arrays can all be used to identify and validate biomarkers. See details here.
In clinical practice, biomarkers can be used to identify risk and
susceptibility, diagnose a disease, assess disease severity or progression,
classify patients, guide treatment, and predict prognosis. In drug development
and the pharmaceutical industry, biomarkers can be used to predict toxicity,
safety, or efficacy of a drug. Biomarkers can be categorized as target,
mechanism and clinical to indicate if a drug hits its intended target, alters
any mechanisms and if it is effective in vivo. Biomarkers can be also classified
into three types: type 0 - natural history markers, type 1 - biological or drug
activity markers, and type 2 - surrogate markers. Type 0 biomarkers measure the
natural history of a disease and should correlate over time with known clinical
indicators. They can be characterized in phase 0 clinical trials. Symptoms over
the full range of a disease and most prognosis markers are type 0 biomarkers. In
most cases, type 1 biomarkers are the markers that capture the effects of a
therapeutic intervention in accordance with its mechanism of action. A type 2
biomarker (the NIH defines a type 2 biomarker or a surrogate marker as a
biomarker intended to substitute for a clinical endpoint) is a measure of effect
of a certain treatment that may correlate with a real clinical endpoint but does
not necessarily have a guaranteed relationship. The most commonly used surrogate
marker is blood cholesterol level.
Biomarker application in drug development is driven by the increasing need to
define diseases, achieve earlier and better drug safety and efficacy, reduce
cost, and inform regulatory decision-making. Advances in molecular medicine have
resulted in the explosive growth in new biomarker discovery and increased the
scope of biomarker knowledge. Much of the advancement is related to new
technologies such as genomics, proteomics, and imaging. For example, in genomics
scientists are actively looking for unique molecular signatures in diseases.
Biomarkers are critical to realizing a new era of "personalized
medicine." In other words, biomarkers will be essential for deciding what
treatments would be appropriate for individual patients.
A prognostic biomarker provides information about the patients' overall
outcome, regardless of therapy while a predictive biomarker gives information
about the effect of a therapeutic intervention. Well-known predictive biomarkers
are ER, PR and HER2/neu in breast cancer, BCR-ABL fusion protein in chronic
myeloid leukaemia, c-KIT mutations in gastro-intestinal stromal tumor (GIST),
and EGFR1 mutations in non-small cell lung cancer (NSCLC). The cytochrome P450 (CYP)
system of drug-metabolizing enzymes represents the best studied set of
pharmaceutically important predictive markers (CYP2C9, CYP2C19, CYP2D6…). In
general, some biomarkers can be used to predict the natural course of a disease,
indicating whether the outcome for the patient is likely to be good or poor
(prognosis); other biomarkers can help doctors to decide which patients are
likely to respond to what treatment (prediction), and at what dose it might be
most effective (pharmacodynamics).
Epigenetics is one of the fastest-growing areas of life science. Aberrant DNA
methylation, histone modification, chromatin remodeling, and microRNA regulation
are the main types of epigenetic alterations in diseases. Much, if not most, of
the basic research in epigenetics carried out so far and almost all the clinical
applications stemming from this research to date are in the field of oncology.
Four epigenetics-based FDA-approved drugs are on the market - two demethylating
agents [they are Vidaza and Dacogen for treatment of myelodysplastic syndromes
(MDS). Roughly 30% of patients with MDS progress to acute myelogenous leukemia
(AML) ] and two histone deacetylase (HDAC) inhibitors [Zolinza (vorinostat, SAHA)
for the treatment of cutaneous T-cell lymphoma, and Depakote, Depakote ER,
Depakene, Depacon, Stavzor (valproic acid) for the treatment of bipolar
disorder, seizures and migraine headaches]. The diagnostic sector of the
industry is expected to experience a dramatic growth phase over the next few
years, driven in part by continuing advances in epigenetic biomarker discovery
and technology.
MicroRNAs recently have shown the potential to be used as clinical biomarkers
for a wide range of diseases. MicroRNA signatures can potentially predict
colorectal cancer recurrence in stage II patients. Similar results have been
reported for pancreatic, breast, lung, and liver cancer. Circulating microRNAs
from blood samples also provided reliable diagnosis for multiple sclerosis (MS)
and diabetes. Circulating microRNA-1 may also be a novel, independent biomarker
for diagnosis of acute myocardial infarction (AMI).
Although much progress in epigenetic markers has occurred, serum biomarkers
are still the most routinely used in clinical practice. The most widely used
biomarker for prostate cancer detection is prostate-specific antigen (PSA).
Carcinoembryonic antigen (CEA) is another widely used biomarker that is
monitored in patients with colorectal, breast, lung, or pancreatic cancer.
Monitoring CEA after colon cancer surgery is an effective way of determining the
adequacy of post-operative therapy.
The lack of good quality samples can be a stumbling block for biomarker
discovery. Rarely are enough samples collected in a clinical trial and those
collected samples are usually fixed in formalin which can affect their ability
to be analyzed. There is a strong need to develop biomarker diagnostics that can
reliably and easily be used on the paraffin-embedded or formalin-fixed tissues.
SABiosciences provides a new and successful RT2 FFPE (formalin-fixed
paraffin-embedded) PreAMP technology that combines a novel RNA extraction
protocol with a powerful pre-amplification of a pathway-focused set of genes for
real-time PCR analysis. With this new technology, FFPE RNA can finally serve as
a useful source for gene profiling studies for retrospective biomarker
identification.
The spectrum of biomarkers suggests that no single technology or discipline
can cover the whole biomarker discovery field. It takes collaborative efforts in
the fields of genomics, epigenomics, proteomics, metabolomics, epidemiology, and
methodologies such as imaging, cytometry, and histology.
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Recommended Pathways For Biomarkers
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