Proteomics: improving biomarker translation to modern medicine?
© BioMed Central Ltd 2013
Published: 27 February 2013
Biomarkers are defined as 'measurable characteristics that reflect physiological, pharmacological, or disease processes' according to the European Medicines Agency . The ideal platforms for biomarker discovery include genomic, transcriptomic, proteomic, metabonomic and imaging analyses. However, most biomarkers used in clinical studies are based on proteomic applications as the majority of current drug targets are proteins, such as G protein-coupled receptors, ion channels, enzymes and components of hormone signaling pathways . Furthermore, linking the results of biomarker studies using protein-protein interaction approaches can assist in systems biology approaches and could lead to hypothesis generation and identification of new drug targets .
Currently, there are only a few molecular tests that can predict response to certain treatments and these are mainly restricted to the field of oncology. Perhaps the best example of this is human epidermal growth factor receptor 2 (HER2) expression in breast cancer cells. This cell surface receptor can be blocked by the antibody-based therapeutic Herceptin™ (trastuzumab) . Such successes have raised hopes for discovery of biomarkers in other areas of medicine. However, in most cases, the claims for other novel biomarker candidates have not been proven in validation studies or in clinical trials. Potential reasons for this include deficiencies in design and analysis, the problem that drug targets and biomarkers may not be causal to the disease but rather a result of the disease process or a co-morbid effect, a lack of congruence of preclinical models with the human disease, or even because of factors such as the incorrect enrolment of patients in clinical trials who are too advanced in their disease stage to show any response to potential therapeutics . Nonetheless, a consensus has now been reached for testing biomarker candidates in the earliest stages of a disorder, as described recently for neurodegenerative conditions such as Alzheimer's disease .
The suggestion that biomarker research has not lived up to the initial hype comes from the fact that publicized multiple 'breakthrough' tests have still not reached the market. This has led to skepticism from clinicians, scientists and regulatory agencies, which might make the introduction of valid biomarkers into clinical diagnostics or the drug discovery industry even more difficult. This is due in part to the lack of a connection between biomarker discovery with technologies for validation and translation to platforms that provide accuracy and ease of use in a clinical setting . Apart from some biomarkers in the field of cancer research, most have not been validated and have now faded from the spotlight. Major cancer biomarkers that have received Food and Drug Administration (FDA) approval over the last few decades include prostate-specific antigen (PSA) for prostate cancer, carcinoembryonic antigen (CA)-125 for ovarian cancer and CA-19-9 for pancreatic cancer . However, apart from the possible exception of PSA, most of these have been used mainly for monitoring treatment response and are not suitable for early diagnosis.
Three types of biomarkers for use in clinical studies
Evidence for scientific proof of concept
Probable valid biomarkers
Measurement in an established analytical test system and evidence explaining the clinical significance of the results
Known valid biomarkers
Biomarker test results should be accurately replicated at different sites, laboratories or agencies in cross-validation experiments
It is clear that there is still a long way to go before the potential of proteomics can be entirely utilized in the preclinical and clinical fields, slowly progressing from bench to bedside and back again in an ongoing endeavor to improve patient outcomes. The tight regulations and concerted efforts outlined above will be essential in this journey. However, there is now optimism that further technological developments and interdisciplinary approaches will continue to advance the field of biomarkers so that its impact on modern medicine can be fully realized.
This work was supported by the Stanley Medical Research Institute (SMRI), the European Union FP7 SchizDX research program (grant reference 223427) and the NeuroBasic grant from the Dutch government. MGG is funded by a Gonville and Caius College - Cambridge Home and European Scholarship and an EPSCR doctoral training grant.
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