Abstract
Advances in mass spectrometry, proteomics, protein bioanalytical approaches, and biochemistry have led to a rapid evolution and expansion in the area of mass spectrometry-based biomarker discovery and development. The last decade has also seen significant progress in establishing accepted definitions, guidelines, and criteria for the analytical validation, acceptance, and qualification of biomarkers. These advances have coincided with a decreased return on investment for pharmaceutical research and development and an increasing need for better early decision making tools. Empowering development teams with tools to measure a therapeutic interventions impact on disease state and progression, measure target engagement, and to confirm predicted pharmacodynamic effects is critical to efficient data-driven decision making. Appropriate implementation of a biomarker or a combination of biomarkers can enhance understanding of a drugs mechanism, facilitate effective translation from the preclinical to clinical space, enable early proof of concept and dose selection, and increase the efficiency of drug development. Here we will provide descriptions of the different classes of biomarkers that have utility in the drug development process as well as review specific, protein-centric, mass spectrometry-based approaches for the discovery of biomarkers and development of targeted assays to measure these markers in a selective and analytically precise manner.
Keywords
- Multiple Reaction Monitoring
- Drug Development Process
- Metabolic Label
- Target Engagement
- Stable Isotope Dilution
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aebersold R, Mann M (2003) Mass spectrometry-based proteomics. Nature 422(6928):198–207
Anderson NL, Anderson NG (2002) The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1(11):845–867
Anderson NL, Anderson NG, Haines LR, Hardie DB, Olafson RW, Pearson TW (2004) Mass spectrometric quantitation of peptides and proteins using stable isotope standards and capture by anti-peptide antibodies (SISCAPA). J Proteome Res 3(2):235–244
Baldwin MA (2004) Protein identification by mass spectrometry: issues to be considered. Mol Cell Proteomics 3(1):1–9
Barr JR, Maggio VL, Patterson DG Jr, Cooper GR, Henderson LO, Turner WE, Smith SJ, Hannon WH, Needham LL, Sampson EJ (1996) Isotope dilution—mass spectrometric quantification of specific proteins: model application with apolipoprotein A-I. Clin Chem 42(10):1676–1682
Batalha IL, Lowe CR, Roque AC (2012) Platforms for enrichment of phosphorylated proteins and peptides in proteomics. Trends Biotechnol 30(2):100–110
Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69(3):89–95
Breitling R (2006) Biological microarray interpretation: the rules of engagement. Biochim Biophys Acta 1759(7):319–327
Carr S, Aebersold R, Baldwin M, Burlingame A, Clauser K, Nesvizhskii A (2004) The need for guidelines in publication of peptide and protein identification data: working group on publication guidelines for peptide and protein identification data. Mol Cell Proteomics 3(6):531–533
Carser JE, Quinn JE, Michie CO, O’Brien EJ, Mccluggage WG, Maxwell P, Lamers E, Lioe TF, Williams AR, Kennedy RD, Gourley C, Harkin DP (2011) BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer. Gynecol Oncol 123(3):492–498
Chandra H, Reddy PJ, Srivastava S (2011) Protein microarrays and novel detection platforms. Expert Rev Proteomics 8(1):61–79
Chung C, Christianson M (2014) Predictive and prognostic biomarkers with therapeutic targets in breast, colorectal, and non-small cell lung cancers: a systemic review of current development, evidence, and recommendation. J Oncol Pharm Pract 20(1):11–28
Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 350(14):1387–1397
Desiderio DM, Kai M (1983) Preparation of stable isotope-incorporated peptide internal standards for field desorption mass spectrometry quantification of peptides in biologic tissue. Biomed Mass Spectrom 10(8):471–479
Desiderio DM, Kai M, Tanzer FS, Trimble J, Wakelyn C (1984) Measurement of enkephalin peptides in canine brain regions, teeth, and cerebrospinal fluid with high-performance liquid chromatography and mass spectrometry. J Chromatogr 297:245–260
Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM (2001) Delineation of prognostic biomarkers in prostate cancer. Nature 412(6849):822–826
Dimasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22(2):151–185
Elbert DL, Mawuenyega KG, Scott EA, Wildsmith KR, Bateman RJ (2008) Stable isotope labeling tandem mass spectrometry (SILT): integration with peptide identification and extension to data-dependent scans. J Proteome Res 7(10):4546–4556
Fang X, Zhang WW (2008) Affinity separation and enrichment methods in proteomic analysis. J Proteomics 71(3):284–303
Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2(7):566–580
Gatlin CL, Kleemann GR, Hays LG, Link AJ, Yates JR III (1998) Protein identification at the low femtomole level from silver-stained gels using a new fritless electrospray interface for liquid chromatography-microspray and nanospray mass spectrometry. Anal Biochem 263(1):93–101
Gillette MA, Mani DR, Carr SA (2005) Place of pattern in proteomic biomarker discovery. J Proteome Res 4(4):1143–1154
Gold L, Ayers D, Bertino J, Bock C, Bock A, Brody EN, Carter J, Dalby AB, Eaton BE, Fitzwater T, Flather D, Forbes A, Foreman T, Fowler C, Gawande B, Goss M, Gunn M, Gupta S, Halladay D, Heil J, Heilig J, Hicke B, Husar G, Janjic N, Jarvis T, Jennings S, Katilius E, Keeney TR, Kim N, Koch TH, Kraemer S, Kroiss L, Le N, Levine D, Lindsey W, Lollo B, Mayfield W, Mehan M, Mehler R, Nelson SK, Nelson M, Nieuwlandt D, Nikrad M, Ochsner U, Ostroff RM, Otis M, Parker T, Pietrasiewicz S, Resnicow DI, Rohloff J, Sanders G, Sattin S, Schneider D, Singer B, Stanton M, Sterkel A, Stewart A, Stratford S, Vaught JD, Vrkljan M, Walker JJ, Watrobka M, Waugh S, Weiss A, Wilcox SK, Wolfson A, Wolk SK, Zhang C, Zichi D (2010) Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One 5(12):e15004
Grimwood S, Hartig PR (2009) Target site occupancy: emerging generalizations from clinical and preclinical studies. Pharmacol Ther 122(3):281–301
Gustavsson N, Greber B, Kreitler T, Himmelbauer H, Lehrach H, Gobom J (2005) A proteomic method for the analysis of changes in protein concentrations in response to systemic perturbations using metabolic incorporation of stable isotopes and mass spectrometry. Proteomics 5(14):3563–3570
Gutman S, Kessler LG (2006) The US Food and Drug Administration perspective on cancer biomarker development. Nat Rev Cancer 6(7):565–571
Gygi SP, Rist B, Gerber SA, Turecek F, Gelb MH, Aebersold R (1999) Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol 17(10):994–999
Rang HP (2006) Pharmacology: its role in drug discovery. In: Rang HP (ed) Drug discovery and development: technology in transition. Elsevier, Philadelphia
Hakimi A, Auluck J, Jones GD, Ng LL, Jones DJ (2014) Assessment of reproducibility in depletion and enrichment workflows for plasma proteomics using label-free quantitative data-independent LC-MS. Proteomics 14(1):4–13
Institute Of Medicine (US) Forum On Drug Discovery, D. A. T (2009) Accelerating the development of biomarkers for drug safety: workshop summary. The National Academies Collection: reports funded by National Institutes of Health. National Academies Press (US), Washington
Jaffe JD, Keshishian H, Chang B, Addona TA, Gillette MA, Carr SA (2008) Accurate inclusion mass screening: a bridge from unbiased discovery to targeted assay development for biomarker verification. Mol Cell Proteomics 7(10):1952–1962
Peters KE, Walters CC, Moldowan JM (2007) The biomarker guide: biomarkers and isotopes in the environment and human history, 2nd edn. Cambridge University Press, Cambridge
Kelleher NL (2004) Top-down proteomics. Anal Chem 76(11):197A–203A
Krijgsveld J, Ketting RF, Mahmoudi T, Johansen J, Artal-Sanz M, Verrijzer CP, Plasterk RH, Heck AJ (2003) Metabolic labeling of C. elegans and D. melanogaster for quantitative proteomics. Nat Biotechnol 21(8):927–931
Krishna R, Herman G, Wagner JA (2008) Accelerating drug development using biomarkers: a case study with sitagliptin, a novel DPP4 inhibitor for type 2 diabetes. AAPS J 10(2):401–409
Li Q (2010) Assigning significance in label-free quantitative proteomics to include single-peptide-hit proteins with low replicates. Int J Proteomics 2010
Mahajan R, Gupta K (2010) Food and drug administration’s critical path initiative and innovations in drug development paradigm: challenges, progress, and controversies. J Pharm Bioallied Sci 2(4):307–313
Marquette CA, Corgier BP, Blum LJ (2012) Recent advances in multiplex immunoassays. Bioanalysis 4(8):927–936
Marrer E, Dieterle F (2010) Impact of biomarker development on drug safety assessment. Toxicol Appl Pharmacol 243(2):167–179
Matthews PM, Rabiner EA, Passchier J, Gunn RN (2012) Positron emission tomography molecular imaging for drug development. Br J Clin Pharmacol 73(2):175–186
Mazur MT, Cardasis HL, Spellman DS, Liaw A, Yates NA, Hendrickson RC (2010) Quantitative analysis of intact apolipoproteins in human HDL by top-down differential mass spectrometry. Proc Natl Acad Sci U S A 107(17):7728–7733
Meng F, Wiener MC, Sachs JR, Burns C, Verma P, Paweletz CP, Mazur MT, Deyanova EG, Yates NA, Hendrickson RC (2007) Quantitative analysis of complex peptide mixtures using FTMS and differential mass spectrometry. J Am Soc Mass Spectrom 18(2):226–233
Mor G, Visintin I, Lai Y, Zhao H, Schwartz P, Rutherford T, Yue L, Bray-Ward P, Ward DC (2005) Serum protein markers for early detection of ovarian cancer. Proc Natl Acad Sci U S A 102(21):7677–7682
Motoyama A, Yates JR III (2008) Multidimensional LC separations in shotgun proteomics. Anal Chem 80(19):7187–7193
Nesvizhskii AI (2010) A survey of computational methods and error rate estimation procedures for peptide and protein identification in shotgun proteomics. J Proteomics 73(11):2092–2123
Nesvizhskii AI, Aebersold R (2004) Analysis, statistical validation and dissemination of large-scale proteomics datasets generated by tandem MS. Drug Discov Today 9(4):173–181
Ng PC, Kirkness EF (2010) Whole genome sequencing. Methods Mol Biol 628:215–226
O’Connor JP, Jackson A, Asselin MC, Buckley DL, Parker GJ, Jayson GC (2008) Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives. Lancet Oncol 9(8):766–776
Ong SE, Blagoev B, Kratchmarova I, Kristensen DB, Steen H, Pandey A, Mann M (2002) Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics. Mol Cell Proteomics 1(5):376–386
Ong SE, Foster LJ, Mann M (2003) Mass spectrometric-based approaches in quantitative proteomics. Methods 29(2):124–130
Paweletz CP, Wiener MC, Bondarenko AY, Yates NA, Song Q, Liaw A, Lee AY, Hunt BT, Henle ES, Meng F, Sleph HF, Holahan M, Sankaranarayanan S, Simon AJ, Settlage RE, Sachs JR, Shearman M, Sachs AB, Cook JJ, Hendrickson RC (2010) Application of an end-to-end biomarker discovery platform to identify target engagement markers in cerebrospinal fluid by high resolution differential mass spectrometry. J Proteome Res 9(3):1392–1401
Pratt JM, Petty J, Riba-Garcia I, Robertson DH, Gaskell SJ, Oliver SG, Beynon RJ (2002) Dynamics of protein turnover, a missing dimension in proteomics. Mol Cell Proteomics 1(8):579–591
Rabilloud T (2002) Two-dimensional gel electrophoresis in proteomics: old, old fashioned, but it still climbs up the mountains. Proteomics 2(1):3–10
Rawlins MD (2004) Cutting the cost of drug development? Nat Rev Drug Discov 3(4):360–364
Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24(8):971–983
Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S, Khainovski N, Pillai S, Dey S, Daniels S, Purkayastha S, Juhasz P, Martin S, Bartlet-Jones M, He F, Jacobson A, Pappin DJ (2004) Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol Cell Proteomics 3(12):1154–1169
Sadygov RG, Liu H, Yates JR (2004) Statistical models for protein validation using tandem mass spectral data and protein amino acid sequence databases. Anal Chem 76(6):1664–1671
Simon GM, Niphakis MJ, Cravatt BF (2013) Determining target engagement in living systems. Nat Chem Biol 9(4):200–205
Siuti N, Kelleher NL (2007) Decoding protein modifications using top-down mass spectrometry. Nat Methods 4(10):817–821
Snijders AP, De Vos MG, Wright PC (2005) Novel approach for peptide quantitation and sequencing based on 15N and 13C metabolic labeling. J Proteome Res 4(2):578–585
Staes A, Demol H, Van Damme J, Martens L, Vandekerckhove J, Gevaert K (2004) Global differential non-gel proteomics by quantitative and stable labeling of tryptic peptides with oxygen-18. J Proteome Res 3(4):786–791
States DJ, Omenn GS, Blackwell TW, Fermin D, Eng J, Speicher DW, Hanash SM (2006) Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study. Nat Biotechnol 24(3):333–338
Swatton JE, Prabakaran S, Karp NA, Lilley KS, Bahn S (2004) Protein profiling of human postmortem brain using 2-dimensional fluorescence difference gel electrophoresis (2-D DIGE). Mol Psychiatry 9(2):128–143
Tello-Montoliu A, Marin F, Roldan V, Mainar L, Lopez MT, Sogorb F, Vicente V, Lip GY (2007) A multimarker risk stratification approach to non-ST elevation acute coronary syndrome: implications of troponin T, CRP, NT pro-BNP and fibrin D-dimer levels. J Intern Med 262(6):651–658
Thompson A, Schafer J, Kuhn K, Kienle S, Schwarz J, Schmidt G, Neumann T, Johnstone R, Mohammed AK, Hamon C (2003) Tandem mass tags: a novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. Anal Chem 75(8):1895–1904
Tiller PR, Cunniff J, Land AP, Schwartz J, Jardine I, Wakefield M, Lopez L, Newton JF, Burton RD, Folk BM, Buhrman DL, Price P, Wu D (1997) Drug quantitation on a benchtop liquid chromatography-tandem mass spectrometry system. J Chromatogr A 771(1–2):119–125
Villanueva J, Philip J, Entenberg D, Chaparro CA, Tanwar MK, Holland EC, Tempst P (2004) Serum peptide profiling by magnetic particle-assisted, automated sample processing and MALDI-TOF mass spectrometry. Anal Chem 76(6):1560–1570
Visscher PM, Brown MA, Mccarthy MI, Yang J (2012) Five years of GWAS discovery. Am J Hum Genet 90(1):7–24
Wagner JA (2008) Strategic approach to fit-for-purpose biomarkers in drug development. Annu Rev Pharmacol Toxicol 48:631–651
Whitelegge JP (2013) Integral membrane proteins and bilayer proteomics. Anal Chem 85(5):2558–2568
Wieboldt R, Campbell DA, Henion J (1998) Quantitative liquid chromatographic-tandem mass spectrometric determination of orlistat in plasma with a quadrupole ion trap. J Chromatogr B Biomed Sci Appl 708(1–2):121–129
Wong DF, Tauscher J, Grunder G (2009) The role of imaging in proof of concept for CNS drug discovery and development. Neuropsychopharmacology 34(1):187–203
Wu CC, Maccoss MJ, Howell KE, Matthews DE, Yates JR III (2004) Metabolic labeling of mammalian organisms with stable isotopes for quantitative proteomic analysis. Anal Chem 76(17):4951–4959
Yao X, Freas A, Ramirez J, Demirev PA, Fenselau C (2001) Proteolytic 18O labeling for comparative proteomics: model studies with two serotypes of adenovirus. Anal Chem 73(13):2836–2842
Yost RA, Perchalski RJ, Brotherton HO, Johnson JV, Budd MB (1984) Pharmaceutical and clinical analysis by tandem mass spectrometry. Talanta 31(10 Pt 2):929–935
Zanivan S, Krueger M, Mann M (2012) In vivo quantitative proteomics: the SILAC mouse. Methods Mol Biol 757:435–450
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Miller, R.A., Spellman, D.S. (2014). Mass Spectrometry-Based Biomarkers in Drug Development. In: Woods, A., Darie, C. (eds) Advancements of Mass Spectrometry in Biomedical Research. Advances in Experimental Medicine and Biology, vol 806. Springer, Cham. https://doi.org/10.1007/978-3-319-06068-2_16
Download citation
DOI: https://doi.org/10.1007/978-3-319-06068-2_16
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-06067-5
Online ISBN: 978-3-319-06068-2
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)