title: Biomarker discovery in biological fluids.
abstract: Discovery of novel protein biomarkers is essential for successful drug discovery and development. These novel protein biomarkers may aid accelerated drug efficacy, response, or toxicity decision making based on their enhanced sensitivity and/or specificity. These biomarkers, if necessary, could eventually be converted into novel diagnostic marker assays. Proteomic platforms developed over the past few years have given us the ability to rapidly identify novel protein biomarkers in various biological matrices from cell cultures (lysates, supernatants) to human clinical samples (serum, plasma, and urine). In this article, we delineate an approach to biomarker discovery. This approach is divided into three steps, (i) identification of markers, (ii) prioritization of identified markers, and (iii) preliminary validation (qualification) of prioritized markers. Using drug-induced idiosyncratic hepatotoxicity as a case study, the article elaborates methods and techniques utilized during the three steps of biomarker discovery process. The first step involves identification of markers using multi-dimensional protein identification technology. The second step involves prioritization of a subset of marker candidates based on several criteria such as availability of reagent set for assay development and literature association to disease biology. The last step of biomarker discovery involves development of preliminary assays to confirm the bio-analytical measurements from the first step, as well as qualify the marker(s) in pre-clinical models, to initiate future marker validation and development.
authors.affiliation: Clinical Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, P.O. Box 5400, Princeton, NJ 08543, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Gao
authors.forename: Leah-Ann
authors.initials: LA
authors.lastname: Garulacan
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Storm
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Opiteck
authors.forename: Yves
authors.initials: Y
authors.lastname: Dubaquie
authors.forename: Stanley A
authors.initials: SA
authors.lastname: Hefta
authors.forename: Donna M
authors.initials: DM
authors.lastname: Dambach
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Dongre
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015415:Biomarkers / Q000737:chemistry*; D015153:Blotting, Western; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D019295:Computational Biology; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007118:Immunoassay / Q000379:methods; D008099:Liver / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry; D013058:Mass Spectrometry / Q000379:methods; D040081:Protein Array Analysis / Q000379:methods*; D011506:Proteins / Q000737:chemistry / Q000302:isolation & purification*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D012680:Sensitivity and Specificity; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D048948:14-3-3 Proteins; D015415:Biomarkers; D008263:Macrophage Migration-Inhibitory Factors; D011506:Proteins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase