The discovery of new highly sensitive and specific biomarkers for early disease detection and risk stratification coupled with the development of personalized “designer” therapies holds the key to future treatment of complex diseases such as cancer. Mounting evidence confirms that the low molecular weight (LMW) range of the circulatory proteome contains a rich source of information that may be able to detect early stage disease and stratify risk. Current mass spectrometry (MS) platforms can generate a rapid and high resolution portrait of the LMW proteome. Emerging novel nanotechnology strategies to amplify and harvest these LMW biomarkers in vivo or ex vivo will greatly enhance our ability to discover and characterize molecules for early disease detection, subclassification and prognostic capability of current proteomics modalities. Ultimately genetic mutations giving rise to disease are played out and manifested on a protein level, involving derangements in protein function and information flow within diseased cells and the interconnected tissue microenvironment. Newly developed highly sensitive, specific and linearly dynamic reverse phase protein microarray systems are now able to generate circuit maps of information flow through phosphoprotein networks of pure populations of microdissected tumor cells obtained from patient biopsies. We postulate that this type of enabling technology will provide the foundation for the development of individualized combinatorial therapies of molecular inhibitors to target tumor-specific deranged pathways regulating key biologic processes including proliferation, differentiation, apoptosis, immunity and metastasis. Hence future therapies will be tailored to the specific deranged molecular circuitry of an individual patient’s disease. The successful transition of these groundbreaking proteomic technologies from research tools to integrated clinical diagnostic platforms will require ongoing continued development, and optimization with rigorous standardization development and quality control procedures.
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References
E. S. Lander et al. (2001) ArticleTitleInitial sequencing and analysis of the human genome Nature 409 IssueID6822 860–921 Occurrence Handle10.1038/35057062 Occurrence Handle11237011
Venter, J. C. et al.
J. L. Badano N. Katsanis (2002) ArticleTitleBeyond Mendel: an evolving view of human genetic disease transmission Nat. Rev. Genet 3 IssueID10 779–789 Occurrence Handle10.1038/nrg910 Occurrence Handle12360236
L. M. Staudt (2002) ArticleTitleGene expression profiling of lymphoid malignancies Annu Rev Med 53 303–318 Occurrence Handle10.1146/annurev.med.53.082901.103941 Occurrence Handle11818476
M. A. Shipp et al. (2002) ArticleTitleDiffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning Nat. Med 8 IssueID1 68–74 Occurrence Handle10.1038/nm0102-68 Occurrence Handle11786909
S. S. Dave et al. (2004) ArticleTitlePrediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells N. Engl. J. Med 351 IssueID21 2159–2169 Occurrence Handle10.1056/NEJMoa041869 Occurrence Handle15548776
D. Singh et al. (2002) ArticleTitleGene expression correlates of clinical prostate cancer behavior Cancer Cell 1 IssueID2 203–209 Occurrence Handle10.1016/S1535-6108(02)00030-2 Occurrence Handle12086878
T. Sorlie et al. (2003) ArticleTitleRepeated observation of breast tumor subtypes in independent gene expression data sets Proc. Natl. Acad. Sci. USA 100 IssueID14 8418–8423 Occurrence Handle10.1073/pnas.0932692100 Occurrence Handle12829800
D. R. Schwartz et al. (2002) ArticleTitleGene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas Cancer Res 62 IssueID16 4722–4729 Occurrence Handle12183431
E. F. Petricoin et al. (2002) ArticleTitleClinical proteomics: translating benchside promise into bedside reality Nat. Rev. Drug Discov 1 IssueID9 683–695 Occurrence Handle10.1038/nrd891 Occurrence Handle12209149
E. F. Petricoin L. A. Liotta (2004) ArticleTitleSELDI-TOF-based serum proteomic pattern diagnostics for early detection of cancer Curr. Opin. Biotechnol 15 IssueID1 24–30 Occurrence Handle10.1016/j.copbio.2004.01.005 Occurrence Handle15102462
K. P. Rosenblatt et al. (2004) ArticleTitleSerum proteomics in cancer diagnosis and management Annu. Rev. Med 55 97–112 Occurrence Handle10.1146/annurev.med.55.091902.105237 Occurrence Handle14746511
A. V. Rapkiewicz et al. (2004) ArticleTitleBiomarkers of ovarian tumours Eur. J. Cancer 40 IssueID17 2604–2612 Occurrence Handle10.1016/j.ejca.2004.05.021 Occurrence Handle15541961
E. F. Petricoin et al. (2002) ArticleTitleUse of proteomic patterns in serum to identify ovarian cancer Lancet 359 IssueID9306 572–577 Occurrence Handle10.1016/S0140-6736(02)07746-2 Occurrence Handle11867112
Conrads, T. P., et al. (2004) High-resolution serum proteomic features for ovarian cancer detection. Endocrine Related Cancer (in press).
J. Li et al. (2002) ArticleTitleProteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer Clin. Chem 48 IssueID8 1296–1304 Occurrence Handle12142387
D. K. Ornstein et al. (2004) ArticleTitleSerum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 Ng/Ml J. Urol 172 IssueID4, Part 1 of 2 1302–1305 Occurrence Handle10.1097/01.ju.0000139572.88463.39 Occurrence Handle15371828
E. F. Petricoin Suffix3rd et al. (2002) ArticleTitleSerum proteomic patterns for detection of prostate cancer J. Natl. Cancer Inst 94 IssueID20 1576–1578 Occurrence Handle12381711
E. F. Petricoin D. K. Ornstein L. A. Liotta (2004) ArticleTitleClinical proteomics: applications for prostate cancer biomarker discovery and detection Urol. Oncol 22 IssueID4 322–328 Occurrence Handle15283891
J. Prados et al. (2004) ArticleTitleMining mass spectra for diagnosis and biomarker discovery of cerebral accidents Proteomics 4 IssueID8 2320–2332 Occurrence Handle10.1002/pmic.200400857 Occurrence Handle15274126
W. Clarke et al. (2003) ArticleTitleCharacterization of renal allograft rejection by urinary proteomic analysis Ann. Surg 237 IssueID5 660–664 Occurrence Handle10.1097/00000658-200305000-00008 Occurrence Handle12724632
O. Carrette et al. (2003) ArticleTitleA panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease Proteomics 3 IssueID8 1486–1494 Occurrence Handle10.1002/pmic.200300470 Occurrence Handle12923774
E. F. Petricoin et al. (2004) ArticleTitleLessons from Kitty Hawk: from feasibility to routine clinical use for the field of proteomic pattern diagnostics Proteomics 4 IssueID8 2357–2360 Occurrence Handle10.1002/pmic.200400865 Occurrence Handle15274129
J. D. Wulfkuhle L. A. Liotta E. F. Petricoin (2003) ArticleTitleProteomic applications for the early detection of cancer Nat. Rev. Cancer 3 IssueID4 267–275 Occurrence Handle10.1038/nrc1043 Occurrence Handle12671665
E. F. Petricoin L. A. Liotta (2004) ArticleTitleProteomic approaches in cancer risk and response assessment Trends Mol. Med 10 IssueID2 59–64 Occurrence Handle10.1016/j.molmed.2003.12.006 Occurrence Handle15102358
L. A. Liotta E. C. Kohn (2001) ArticleTitleThe microenvironment of the tumour–host interface Nature 411 IssueID6835 375–379 Occurrence Handle10.1038/35077241 Occurrence Handle11357145
L. A. Liotta M. Ferrari E. Petricoin (2003) ArticleTitleClinical proteomics: written in blood Nature 425 IssueID6961 905 Occurrence Handle10.1038/425905a Occurrence Handle14586448
A. I. Mehta et al. (2003) ArticleTitleBiomarker amplification by serum carrier protein binding Disease Markers 19 IssueID1 1–10 Occurrence Handle14757941
D. H. Geho et al. (2004) ArticleTitleOpportunities for nanotechnology-based innovation in tissue proteomics Biomed. Microdevices 6 IssueID3 231–239 Occurrence Handle10.1023/B:BMMD.0000042053.51016.b4 Occurrence Handle15377833
J. M. Nam C. S. Thaxton C. A. Mirkin (2003) ArticleTitleNanoparticle-based bio-bar codes for the ultrasensitive detection of proteins Science 301 1884–1886 Occurrence Handle10.1126/science.1088755 Occurrence Handle14512622
K. R. Calvo et al. (2004) ArticleTitleMolecular profiling provides evidence of primary mediastinal large B-cell lymphoma as a distinct entity related to classic Hodgkin lymphoma: implications for mediastinal gray zone lymphomas as an intermediate form of B-cell lymphoma Adv. Anat. Pathol 11 IssueID5 227–238 Occurrence Handle10.1097/01.pap.0000138144.11635.f8 Occurrence Handle15322489
E. F. Petricoin L. A. Liotta (2003) ArticleTitleClinical applications of proteomics J. Nutr 133 IssueID7 Suppl 2476S–2484S Occurrence Handle12840227
L. A. Liotta E. C. Kohn E. F. Petricoin (2001) ArticleTitleClinical proteomics: personalized molecular medicine JAMA 286 IssueID18 2211–2214 Occurrence Handle10.1001/jama.286.18.2211 Occurrence Handle11710876
S. H. Moolgavkar A. G. Knudson SuffixJr. (1981) ArticleTitleMutation and cancer: a model for human carcinogenesis J. Natl. Cancer Inst 66 IssueID6 1037–1052 Occurrence Handle6941039
D. Hanahan R. A. Weinberg (2000) ArticleTitleThe hallmarks of cancer Cell 100 IssueID1 57–70 Occurrence Handle10.1016/S0092-8674(00)81683-9 Occurrence Handle10647931
M. R. Emmert-Buck et al. (1996) ArticleTitleLaser capture microdissection Science 274 IssueID5289 998–1001 Occurrence Handle10.1126/science.274.5289.998 Occurrence Handle8875945
A. P. Fuller et al. (2003) ArticleTitleLaser capture microdissection and advanced molecular analysis of human breast cancer J. Mammary Gland Biol. Neoplasia 8 IssueID3 335–345 Occurrence Handle10.1023/B:JOMG.0000010033.49464.0c Occurrence Handle14973377
X. J. Ma et al. (2003) ArticleTitleGene expression profiles of human breast cancer progression Proc. Natl. Acad. Sci. USA 100 IssueID10 5974–5979 Occurrence Handle10.1073/pnas.0931261100 Occurrence Handle12714683
C. P. Paweletz L. A. Liotta E. F. Petricoin Suffix3rd (2001) ArticleTitleNew technologies for biomarker analysis of prostate cancer progression: laser capture microdissection and tissue proteomics Urology 57 IssueID4 Suppl 1 160–163 Occurrence Handle10.1016/S0090-4295(00)00964-X Occurrence Handle11295617
D. H. Geho E. F. Petricoin L. A. Liotta (2004) ArticleTitleBlasting into the microworld of tissue proteomics: a new window on cancer Clin. Cancer Res 10 IssueID3 825–827 Occurrence Handle10.1158/1078-0432.CCR-1223-3 Occurrence Handle14871957
C. P. Paweletz et al. (2000) ArticleTitleRapid protein display profiling of cancer progression directly from human tissue using a protein biochip Drug Develop. Res 49 34–42 Occurrence Handle10.1002/(SICI)1098-2299(200001)49:1<34::AID-DDR6>3.0.CO;2-W
K. Yanagisawa et al. (2003) ArticleTitleProteomic patterns of tumour subsets in non-small-cell lung cancer Lancet 362 IssueID9382 433–439 Occurrence Handle10.1016/S0140-6736(03)14068-8 Occurrence Handle12927430
K. Yanagisawa et al. (2003) ArticleTitleMolecular fingerprinting in human lung cancer Clin. Lung Cancer 5 IssueID2 113–118 Occurrence Handle14596694
S. A. Schwartz et al. (2004) ArticleTitleProtein profiling in brain tumors using mass spectrometry: feasibility of a new technique for the analysis of protein expression Clin. Cancer Res 10 IssueID3 981–987 Occurrence Handle10.1158/1078-0432.CCR-0927-3 Occurrence Handle14871976
V. Espina et al. (2003) ArticleTitleProtein microarrays: molecular profiling technologies for clinical specimens Proteomics 3 IssueID11 2091–2100 Occurrence Handle10.1002/pmic.200300592 Occurrence Handle14595807
L. A. Liotta et al. (2003) ArticleTitleProtein microarrays: meeting analytical challenges for clinical applications Cancer Cell 3 IssueID4 317–325 Occurrence Handle10.1016/S1535-6108(03)00086-2 Occurrence Handle12726858
C. P. Paweletz et al. (2001) ArticleTitleReverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front Oncogene 20 IssueID16 1981–1989 Occurrence Handle10.1038/sj.onc.1204265 Occurrence Handle11360182
P. C. Herrmann et al. (2003) ArticleTitleMitochondrial proteome: altered cytochrome c oxidase subunit levels in prostate cancer Proteomics 3 IssueID9 1801–1810 Occurrence Handle10.1002/pmic.200300461 Occurrence Handle12973739
R. L. Grubb et al. (2003) ArticleTitleSignal pathway profiling of prostate cancer using reverse phase protein arrays Proteomics 3 IssueID11 2142–2146 Occurrence Handle10.1002/pmic.200300598 Occurrence Handle14595813
J. D. Wulfkuhle et al. (2003) ArticleTitleSignal pathway profiling of ovarian cancer from human tissue specimens using reverse-phase protein microarrays Proteomics 3 IssueID11 2085–2090 Occurrence Handle10.1002/pmic.200300591 Occurrence Handle14595806
S. Nishizuka et al. (2003) ArticleTitleProteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays Proc. Natl. Acad. Sci. USA 100 IssueID24 14229–14234 Occurrence Handle10.1073/pnas.2331323100 Occurrence Handle14623978
Petricoin, E. F., et al. (2004) Mapping molecular networks using proteomics: a vision for patient-tailored combination therapy (in submission).
Calvo, K. R., et al. (2004) Clinical proteomics: in vivo molecular signaling profiles of human tumors, pre and post tumor perfusion with experimental chemotherapy (in preparation).
A. Brazma et al. (2001) ArticleTitleMinimum information about a microarray experiment (MIAME)-toward standards for microarray data Nat. Genet 29 IssueID4 365–371 Occurrence Handle10.1038/ng1201-365 Occurrence Handle11726920
A. J. Carlisle et al. (2000) ArticleTitleDevelopment of a prostate cDNA microarray and statistical gene expression analysis package Mol. Carcinogen 28 IssueID1 12–22 Occurrence Handle10.1002/(SICI)1098-2744(200005)28:1<12::AID-MC3>3.0.CO;2-Q
P. Cutler (2003) ArticleTitleProtein arrays: the current state-of-the-art Proteomics 3 IssueID1 3–18 Occurrence Handle10.1002/pmic.200390007 Occurrence Handle12548629
A. Sreekumar et al. (2001) ArticleTitleProfiling of cancer cells using protein microarrays: discovery of novel radiation-regulated proteins Cancer Res 61 IssueID20 7585–7593 Occurrence Handle11606398
J. C. Miller et al. (2003) ArticleTitleAntibody microarray profiling of human prostate cancer sera: antibody screening and identification of potential biomarkers Proteomics 3 IssueID1 56–63 Occurrence Handle10.1002/pmic.200390009 Occurrence Handle12548634
P. Blume-Jensen T. Hunter (2001) ArticleTitleOncogenic kinase signalling Nature 411 IssueID6835 355–365 Occurrence Handle10.1038/35077225 Occurrence Handle11357143
R. Ishizawar S. J. Parsons (2004) ArticleTitlec-Src and cooperating partners in human cancer Cancer Cell 6 IssueID3 209–214 Occurrence Handle10.1016/j.ccr.2004.09.001 Occurrence Handle15380511
M. T. Kloth et al. (2003) ArticleTitleSTAT5b, a mediator of synergism between c-Src and the epidermal growth factor receptor J. Biol. Chem 278 IssueID3 1671–1679 Occurrence Handle10.1074/jbc.M207289200 Occurrence Handle12429742
J. L. Bos (1989) ArticleTitleRas oncogenes in human cancer: a review Cancer Res 49 IssueID17 4682–4689 Occurrence Handle2547513
A. Sparmann D. Bar-Sagi (2004) ArticleTitleRas-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis Cancer Cell 6 IssueID5 447–458 Occurrence Handle10.1016/j.ccr.2004.09.028 Occurrence Handle15542429
A. L. Jones B. Leyland-Jones (2004) ArticleTitleOptimizing treatment of HER2-positive metastatic breast cancer Semin. Oncol 31 IssueID5 Suppl 10 29–34
B. Leyland-Jones (2002) ArticleTitleTrastuzumab: hopes and realities Lancet Oncol 3 IssueID3 137–144 Occurrence Handle10.1016/S1470-2045(02)00676-9 Occurrence Handle11902499
J. S. Sebolt-Leopold (2004) ArticleTitleMEK inhibitors: a therapeutic approach to targeting the Ras-MAP kinase pathway in tumors Curr. Pharm. Des 10 IssueID16 1907–1914 Occurrence Handle10.2174/1381612043384439 Occurrence Handle15180527
P. Traxler (2003) ArticleTitleTyrosine kinases as targets in cancer therapy—successes and failures Expert Opin. Ther. Targets 7 IssueID2 215–234 Occurrence Handle10.1517/14728222.7.2.215 Occurrence Handle12667099
B. J. Druker (2004) ArticleTitleImatinib as a paradigm of targeted therapies Adv. Cancer Res 91 1–30 Occurrence Handlefull_text||10.1016/S0065-230X(04)91001-9 Occurrence Handle15327887
V. Espina et al. (2004) ArticleTitleUse of proteomic analysis to monitor responses to biological therapies Expert Opin. Biol. Ther 4 IssueID1 83–93 Occurrence Handle10.1517/14712598.4.1.83 Occurrence Handle14680471
E. Petricoin et al. (2004) ArticleTitleClinical proteomics: revolutionizing disease detection and patient tailoring therapy J. Proteome Res 3 IssueID2 209–217 Occurrence Handle10.1021/pr049972m Occurrence Handle15113096
J. M. Irish et al. (2004) ArticleTitleSingle cell profiling of potentiated phospho-protein networks in cancer cells Cell 118 IssueID2 217–228 Occurrence Handle10.1016/j.cell.2004.06.028 Occurrence Handle15260991
N. Normanno et al. (2002) ArticleTitleCooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth Ann. Oncol 13 IssueID1 65–72 Occurrence Handle10.1093/annonc/mdf020 Occurrence Handle11863114
Tibes, R., Trent J., and Kurzrock R. (2004) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu. Rev. Pharmacol. Toxicol.
M. Crul et al. (2001) ArticleTitleRas biochemistry and farnesyl transferase inhibitors: a literature survey Anticancer Drugs 12 IssueID3 163–184 Occurrence Handle10.1097/00001813-200103000-00001 Occurrence Handle11290863
P. Traxler et al. (2001) ArticleTitleTyrosine kinase inhibitors: from rational design to clinical trials Med. Res. Rev 21 IssueID6 499–512 Occurrence Handle10.1002/med.1022 Occurrence Handle11607931
E. Zwick J. Bange A. Ullrich (2002) ArticleTitleReceptor tyrosine kinases as targets for anticancer drugs Trends Mol. Med 8 IssueID1 17–23 Occurrence Handle10.1016/S1471-4914(01)02217-1 Occurrence Handle11796262
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Calvo, K.R., Liotta, L.A. & Petricoin, E.F. Clinical Proteomics: From Biomarker Discovery and Cell Signaling Profiles to Individualized Personal Therapy. Biosci Rep 25, 107–125 (2005). https://doi.org/10.1007/s10540-005-2851-3
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DOI: https://doi.org/10.1007/s10540-005-2851-3