Proteomics for biomarkers in clinical studies

The proteome represents the entire protein complement and corresponds to the functional output produced by a cell or system. The proteome is dynamic and an ability to measure it is central to our understanding of normal cellular processes and the mechanisms by which they are disrupted to produce disease states. Within the proteome individual proteins are subjected to a variety of chemical Post translational modifications (PTMs) which affect their cellular location, interacting partners and molecular functions. PTMs can modulate the activity, stability, and function of a protein and are increasingly recognized as important underlying mechanisms for diseases and can be used as biomarkers.

Incorporating proteomics as a biomarker discovery tool into clinical trials by analysing the proteome in a variety of biological matrices including bio-fluids, tissue and cell lines represents an important direction for drug development. It offers the possibility of early disease diagnosis or of early proof-of-action for novel therapies. This requires high throughput, accurate, precise, sensitive and specific tests for discovery and endpoint validation, followed by rapid translation for patient stratification.

Mass spectrometry, as the leading technology for the characterization of proteins, will continue to produce breakthrough advances in the diagnosis and understanding of the role of the proteome in disease. Modern instruments mean that mass spectrometry has become an accessible, reliable, cost effective tool, for clinical trials, with straightforward workflows to facilitate rapid translation of research discoveries into clinical trial settings.

The discovery, verification and validation of novel biomarkers are critical in streamlining clinical development of targeted compounds, and directing the understanding of drug action against specific pathways. Studies are now underway in many diseases to examine subsets of specific pathology microenvironment and those analysis are also applicable to drug development to define the drug effect on specific microenvironment. Successful assay verification and biological efficacy of single biomarker or set of biomarkers will enhance development of potential drug to targetable pathways and lead to selection of individuals most likely to benefit.

The ICH E16 Document (FDA pdf) of August 2011 asserts that the results of assessment with a biomarker can be relied upon to adequately reflect a biological process, response and support the use of a biomarker during drug development, ranging from discovery to through approval. The use of biomarkers has the potential to facilitate the availability of safer and more effective drug, to guide in the dose selection, to enhance their benefit-risk profile and the biomarker qualification assertion should be submitted to regulatory authorities if the biomarker directly or indirectly helps in regulatory decision-making. The biomarker classification was also extended from genomic biomarker (as reported in the ICH E15 document (EMA pdf) of November 2007) to a variety of Biomarker categories (including genomics, proteomics, and imaging).

At Java, we are implementing proteomics in clinical studies, both in client clinical trials, and in our Coronary Artery Disease (CAD) R&D project. We have developed sample acquisition, processing and analysis methods that deliver robust and informative data in clinical settings. We work with the Mass Spectrometry Resource in the UCD Conway Institute to use state of the art instrumentation and analysis methods in clinical research.