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Protein Quantitation through Targeted Mass Spectrometry: The Way Out of Biomarker Purgatory?

¹ Broad Institute of MIT and Harvard, Cambridge, MA, ² The Plasma Proteome Institute, Washington, DC

^aAddress correspondence to these authors at:, Steven A. Carr, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, Fax 01-617-252-1902, E-mail scarr@broad.mit.edu;, Leigh Anderson, Plasma Proteome Institute, P.O. Box 3450, Washington, DC 20009, E-mail leighanderson@plasmaproteome.org

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The enormous potential of biomarkers to revolutionize clinical practice and improve patient care has been well documented (1)(2). Molecular-based diagnostic and prognostic tests, particularly those aimed at protein analytes, could be used to detect disease earlier, enabling treatment to start sooner and possibly cure rather than to merely delay further injury or death. These tools could also be used to stage disease more accurately and to predict response to therapy, thereby helping to select the correct treatment. Biomarkers can also be used to stratify patients for the assessment of new drug therapies and to serve as surrogate endpoints in early-phase drug trials, thereby lowering the overall cost of drug development and producing more effective treatments. Given their high potential therapeutic and financial impacts, that so few new protein biomarkers have been introduced into widespread clinical use recently is, on the surface, surprising. In fact, only 5 new protein markers have been approved by the US Food and Drug Administration in the last 5 years for measurement in plasma or serum [the information on protein markers in Anderson and Anderson, 2002, has been updated with information from the Center for Devices and Radiological Health, US Food and Drug Administration] (3)(4).

The reasons for the dearth of new protein biomarkers are gradually becoming clearer. They are related to the high false-discovery rate of "omics" methods (regardless of the technology used), combined with a lack of robust methods for biomarker verification in large clinical sample sets (5)(6)(7)(8). It is now common for differential analyses of tissue or plasma samples by multidimensional liquid chromatography–tandem mass spectrometry (LC-MS/MS)¹ (the workhorse tool for unbiased discovery) to confidently identify thousands of proteins, hundreds of which can vary in concentration by 5-fold . . . [Full Text of this Article]

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				E. Kuhn, T. Addona, H. Keshishian, M. Burgess, D.R. Mani, R. T. Lee, M. S. Sabatine, R. E. Gerszten, and S. A. Carr Developing Multiplexed Assays for Troponin I and Interleukin-33 in Plasma by Peptide Immunoaffinity Enrichment and Targeted Mass Spectrometry Clin. Chem., June 1, 2009; 55(6): 1108 - 1117. [Abstract] [Full Text] [PDF]