Proteomic Contributions to Personalized Cancer Care*

Cancer impacts each patient and family differently. Our current understanding of the disease is primarily limited to clinical hallmarks of cancer, but many specific molecular mechanisms remain elusive. Genetic markers can be used to determine predisposition to tumor development, but molecularly targeted treatment strategies that improve patient prognosis are not widely available for most cancers. Individualized care plans, also described as personalized medicine, still must be developed by understanding and implementing basic science research into clinical treatment. Proteomics holds great promise in contributing to the prevention and cure of cancer because it provides unique tools for discovery of biomarkers and therapeutic targets. As such, proteomics can help translate basic science discoveries into the clinical practice of personalized medicine. Here we describe how biological mass spectrometry and proteome analysis interact with other major patient care and research initiatives and present vignettes illustrating efforts in discovery of diagnostic biomarkers for ovarian cancer, development of treatment strategies in lung cancer, and monitoring prognosis and relapse in multiple myeloma patients.

[1]  J. Crowley,et al.  International staging system for multiple myeloma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Matthew R Clutter,et al.  High-content single-cell drug screening with phosphospecific flow cytometry. , 2008, Nature chemical biology.

[3]  A. D. Van den Abbeele,et al.  Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. , 2002, The New England journal of medicine.

[4]  Daniela S Krause,et al.  Tyrosine kinases as targets for cancer therapy. , 2005, The New England journal of medicine.

[5]  Leigh Anderson,et al.  Quantitative Mass Spectrometric Multiple Reaction Monitoring Assays for Major Plasma Proteins* , 2006, Molecular & Cellular Proteomics.

[6]  H. R. Bergen,et al.  Elevated levels of phosphorylated fibrinogen-α-isoforms and differential expression of other post-translationally modified proteins in the plasma of ovarian cancer patients , 2006 .

[7]  B. Druker.  Imatinib as a paradigm of targeted therapies , 2003 .

[8]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[9]  John Rush,et al.  A common phosphotyrosine signature for the Bcr-Abl kinase. , 2006, Blood.

[10]  K. Chisholm,et al.  Targeted comparative proteomics by liquid chromatography/matrix-assisted laser desorption/ionization triple-quadrupole mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[11]  Jeffrey R. Whiteaker,et al.  Head-to-head comparison of serum fractionation techniques. , 2007, Journal of proteome research.

[12]  Donald R Schwartz,et al.  Comprehensive proteome analysis of ovarian cancers using liquid phase separation, mass mapping and tandem mass spectrometry: A strategy for identification of candidate cancer biomarkers , 2004, Proteomics.

[13]  B. Mayer,et al.  Quantitative multiplexed profiling of cellular signaling networks using phosphotyrosine-specific DNA-tagged SH2 domains , 2006, Nature Methods.

[14]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[15]  David E. Misek,et al.  Discovery of cancer biomarkers through the use of mouse models. , 2007, Cancer letters.

[16]  H. Jäck,et al.  Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. , 2007, Cancer research.

[17]  S. Barnhill,et al.  CA 125: The past and the Future , 1998, The International journal of biological markers.

[18]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[19]  S. Salmon,et al.  A clinical staging system for multiple myeloma correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival , 1975, Cancer.

[20]  S. Friend,et al.  Cancer Biomarkers—An Invitation to the Table , 2006, Science.

[21]  Usha Menon,et al.  Progress and Challenges in Screening for Early Detection of Ovarian Cancer* , 2004, Molecular & Cellular Proteomics.

[22]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[23]  P. Schwartz,et al.  Is early detection of ovarian cancer possible? , 1995, Annals of medicine.

[24]  R. Nelson,et al.  Investigating diversity in human plasma proteins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Cristina Al-Khalili Szigyarto,et al.  Large-scale proteomics analysis of human ovarian cancer for biomarkers. , 2007, Journal of proteome research.

[26]  R. Orlowski,et al.  Emerging data on the use of anthracyclines in combination with bortezomib in multiple myeloma. , 2007, Clinical lymphoma & myeloma.

[27]  E. Petricoin,et al.  Use of proteomic patterns in serum to identify ovarian cancer , 2002, The Lancet.

[28]  G. Auer,et al.  Two‐dimensional gel analysis of protein expression in ovarian tumors shows a low degree of intratumoral heterogeneity , 1999, Electrophoresis.

[29]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[30]  Alejandro Wolf-Yadlin,et al.  Quantitative proteomic analysis of phosphotyrosine-mediated cellular signaling networks. , 2007, Methods in molecular biology.

[31]  Kimberly Lee,et al.  Phosphoproteomic analysis of AML cell lines identifies leukemic oncogenes. , 2006, Leukemia research.

[32]  M. Meyerson,et al.  Summary Statement: Novel Agents in the Treatment of Lung Cancer: Advances in Epidermal Growth Factor Receptor-Targeted Agents , 2006, Clinical Cancer Research.

[33]  Tony Pawson,et al.  Specificity in Signal Transduction From Phosphotyrosine-SH2 Domain Interactions to Complex Cellular Systems , 2004, Cell.

[34]  M. Piver,et al.  Etiology, biology, and epidemiology of ovarian cancer. , 1994, Seminars in surgical oncology.

[35]  M. Mann,et al.  Temporal analysis of phosphotyrosine-dependent signaling networks by quantitative proteomics , 2004, Nature Biotechnology.

[36]  R. Bast,et al.  The CA 125 tumour-associated antigen: a review of the literature. , 1989, Human reproduction.

[37]  Gerhard Dürnberger,et al.  Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. , 2007, Blood.

[38]  Veronika A. Glukhova,et al.  Contribution of protein fractionation to depth of analysis of the serum and plasma proteomes. , 2007, Journal of proteome research.

[39]  A. Ignatchenko,et al.  A proteome resource of ovarian cancer ascites: integrated proteomic and bioinformatic analyses to identify putative biomarkers. , 2008, Journal of proteome research.

[40]  Ron Bose,et al.  Phosphoproteomic analysis of Her2/neu signaling and inhibition. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[41]  W. Collins,et al.  SCREENING FOR EARLY OVARIAN CANCER , 1988, The Lancet.

[42]  A. Olshen,et al.  Differential exoprotease activities confer tumor-specific serum peptidome patterns. , 2005, The Journal of clinical investigation.

[43]  R. Bast,et al.  Reactivity of a monoclonal antibody with human ovarian carcinoma. , 1981, The Journal of clinical investigation.

[44]  Werner Zolg,et al.  Quantification of C‐reactive protein in the serum of patients with rheumatoid arthritis using multiple reaction monitoring mass spectrometry and 13C‐labeled peptide standards , 2004, Proteomics.

[45]  Ronald J. Moore,et al.  Toward a Human Blood Serum Proteome , 2002, Molecular & Cellular Proteomics.

[46]  Alan Cantor,et al.  Feasibility and efficacy of molecular analysis-directed individualized therapy in advanced non-small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[47]  Lori J Sokoll,et al.  Quantification of fragments of human serum inter-alpha-trypsin inhibitor heavy chain 4 by a surface-enhanced laser desorption/ionization-based immunoassay. , 2006, Clinical chemistry.

[48]  Ronald J Moore,et al.  Ultra-high-efficiency strong cation exchange LC/RPLC/MS/MS for high dynamic range characterization of the human plasma proteome. , 2004, Analytical chemistry.

[49]  Nuzhat Ahmed,et al.  Proteomic tracking of serum protein isoforms as screening biomarkers of ovarian cancer , 2005, Proteomics.

[50]  Matthew E Monroe,et al.  A proteomic study of the HUPO Plasma Proteome Project's pilot samples using an accurate mass and time tag strategy , 2005, Proteomics.

[51]  G. Ragsdell.  Systems , 2002, Economics of Visual Art.

[52]  R. Bast,et al.  OVX1, macrophage‐colony stimulating factor, and CA‐125‐II as tumor markers for epithelial ovarian carcinoma , 2001, Cancer.

[53]  J. Hornaday,et al.  Cancer Facts & Figures 2004 , 2004 .

[54]  Andrew D. Yates,et al.  Somatic mutations of the protein kinase gene family in human lung cancer. , 2005, Cancer research.

[55]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[56]  Xiahui Bi,et al.  Isoelectric focusing technology quantifies protein signaling in 25 cells , 2006, Proceedings of the National Academy of Sciences.

[57]  H Robert Bergen,et al.  Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Akhilesh Pandey,et al.  A functional annotation of subproteomes in human plasma , 2005, Proteomics.

[59]  Sandra A. Moore,et al.  Activating alleles of JAK3 in acute megakaryoblastic leukemia. , 2006, Cancer cell.

[60]  Terry M Therneau,et al.  Prevalence of monoclonal gammopathy of undetermined significance. , 2006, The New England journal of medicine.

[61]  B. Druker.  David A. Karnofsky Award lecture. Imatinib as a paradigm of targeted therapies. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  D. Lauffenburger,et al.  Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks , 2007, Proceedings of the National Academy of Sciences.

[63]  Zhong Zheng,et al.  DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. , 2007, The New England journal of medicine.

[64]  Fuchu He,et al.  Comparison of alternative analytical techniques for the characterisation of the human serum proteome in HUPO Plasma Proteome Project , 2005, Proteomics.

[65]  Richard D. Smith,et al.  Quantitative proteomic approaches for studying phosphotyrosine signaling , 2007, Expert review of proteomics.

[66]  A. Chanan-Khan,et al.  Clinical impact of bortezomib in frontline regimens for patients with multiple myeloma. , 2007, The oncologist.

[67]  K. Coombes,et al.  Direct tandem mass spectrometry reveals limitations in protein profiling experiments for plasma biomarker discovery. , 2005, Journal of proteome research.

[68]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.

[69]  J. Rush,et al.  Immunoaffinity profiling of tyrosine phosphorylation in cancer cells , 2005, Nature Biotechnology.

[70]  Eugene A. Kapp,et al.  Overview of the HUPO Plasma Proteome Project: Results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly‐available database , 2005, Proteomics.

[71]  G. Superti-Furga,et al.  The Btk tyrosine kinase is a major target of the Bcr-Abl inhibitor dasatinib , 2007, Proceedings of the National Academy of Sciences.

[72]  P. Tempst,et al.  A Sequence-specific Exopeptidase Activity Test (SSEAT) for “Functional” Biomarker Discovery*S , 2008, Molecular & Cellular Proteomics.

[73]  Tony Pawson,et al.  High-throughput phosphotyrosine profiling using SH2 domains. , 2007, Molecules and Cells.

[74]  J. Bergquist,et al.  Evaluation of shotgun sequencing for proteomic analysis of human plasma using HPLC coupled with either ion trap or Fourier transform mass spectrometry. , 2003, Journal of proteome research.

[75]  David C Muddiman,et al.  Epithelial ovarian cancer: disease etiology, treatment, detection, and investigational gene, metabolite, and protein biomarkers. , 2007, Journal of proteome research.

[76]  Xiao-Ying Meng,et al.  Classification of cancer types by measuring variants of host response proteins using SELDI serum assays , 2005, International journal of cancer.

[77]  J. Berek,et al.  Ovarian cancer: epidemiology, biology, and prognostic factors. , 2000, Seminars in surgical oncology.

[78]  S. Hanash,et al.  Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study , 2006, Nature Biotechnology.

[79]  M. Mann,et al.  The human urinary proteome contains more than 1500 proteins, including a large proportion of membrane proteins , 2006, Genome Biology.

[80]  R. Bast,et al.  Elevation of multiple serum markers in patients with stage I ovarian cancer. , 1993, Journal of the National Cancer Institute.

[81]  O. Jensen.  Interpreting the protein language using proteomics , 2006, Nature Reviews Molecular Cell Biology.

[82]  G. Auer,et al.  Phenotypic analysis of ovarian carcinoma: Polypeptide expression in benign, borderline and malignant tumors , 1997, International journal of cancer.

[83]  Laura A. Sullivan,et al.  Global Survey of Phosphotyrosine Signaling Identifies Oncogenic Kinases in Lung Cancer , 2007, Cell.

[84]  R. Bast,et al.  Three Biomarkers Identified from Serum Proteomic Analysis for the Detection of Early Stage Ovarian Cancer , 2004, Cancer Research.

[85]  J. Rigas,et al.  Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  Ronald J Moore,et al.  Characterization of the human blood plasma proteome , 2005, Proteomics.

[87]  S. Gygi,et al.  Haptoglobin-α subunit as potential serum biomarker in ovarian cancer: Identification and characterization using proteomic profiling and mass spectrometry , 2003 .

[88]  G. Hall,et al.  Proteomic Profiling Identifies Afamin as a Potential Biomarker for Ovarian Cancer , 2007, Clinical Cancer Research.