Expert Review of Proteomics Downloaded from informahealthcare.com by National Taichung University of Science and Technology on 04/23/14 For personal use only.
SPECIAL FOCUS y Proteomics in translational cancer research
Foreword
Proteomics in translational cancer research: biomarker discovery for clinical applications Expert Rev. Proteomics 11(2), 131–133 (2014)
William CS Cho Department of Clinical Oncology, Health Authority, Hong Kong, China [email protected]
This special focus issue of Expert Review of Proteomics invites key opinion leaders to report their recent findings and views on the important topic of translating potential proteomic biomarkers to clinically useful, regulator-approved biomarkers: a challenging journey. The issue also highlights the difficulties associated with and the way forward in the discovery of proteomic cancer biomarkers for clinical applications, as well as presenting recent original research in the field.
Cancer is one of the most lethal diseases in the world; the estimated mortality is 8.2 million in 2012 [1]. The majority of deaths are due to a lack of early diagnosis and timely treatment. The discovery of cancer biomarkers for early detection and theragnosis is a possible solution to tackle this problem [2]. Early detection and accurate disease classification are key components of most cancer treatment programs and this drives the desire for more effective biomarkers [3]. However, quite a number of patients are diagnosed at advanced stage of cancer due to few sensitive and specific cancer biomarkers being available for clinical care. With the advantages of high sensitivity, specificity and throughput, the use of mass spectrometry (MS)-based proteomic analyses and their clinical applications have been increasingly recognized over the past decade. This technology is used in a wide range of biological and biomedical studies, including the analyses of cancer-specific post-translational modifications and cellular responses. Rapid advances in this high-throughput technology allow the identification of a large number of potential proteomic biomarkers, yet most of these discoveries have not been applied to routine clinical use. Challenges are often accompanied by opportunities. This special focus issue of Expert Review of Proteomics invites key opinion leaders to report their recent findings informahealthcare.com
10.1586/14789450.2014.899908
and views on this important topic, together with discussions of the difficulties associated with and the way forward in the discovery of proteomic cancer biomarkers for clinical applications. Li and Chan contribute an editorial with their expert opinions on why, despite the challenges faced, it is worth the effort to develop a discovered marker into a clinically validated diagnostic biomarker [4]. They comment on how the latest generation of proteomics technologies has allowed the discovery of many new biomarker candidates, but only a few are approved by the US FDA. As the potential rewards for improved cancer treatment are significant, they argue, it is worth the strenuous process to get there. Genomic and proteomic technologies can be used to measure molecular expressions at the transcript and protein levels to provide complementary information that paves the way for systems biology. It is a recent trend to integrate multiple disciplines for the development of panel biomarkers for cancer management. Wang et al. emphasize the merits of integrating proteomics and the emerging methylomic and miRNAomic strategies in the identification and validation of colorectal cancer (CRC) biomarkers [5]. They employ meta-analysis to provide a comprehensive list of previously reported CRCassociated proteins to facilitate further
2014 Informa UK Ltd
ISSN 1478-9450
131
Expert Review of Proteomics Downloaded from informahealthcare.com by National Taichung University of Science and Technology on 04/23/14 For personal use only.
Foreword
Cho
studies. These state-of-the-art systems biology approaches may lead to rapid advances in the discovery and validation of novel panel biomarkers for the early detection and surveillance of CRC. Exosomes secreted by prostate cancer can be isolated from prostatic secretions, seminal fluid, tissue, urine or blood for further proteomic analysis. Investigating the presence of prostatic acid phosphatase and prostate-specific antigen in prostate cancer exosomes, as well as the corresponding glycosylation and lipid profiles of the exosomes may provide a better understanding of the overall function of prostate cancer-derived exosomes in carcinogenesis and disease progression. Drake and Kislinger provide a summary of the ongoing efforts to characterize the proteome of unique prostate cancer-associated exosomes and their potential application in biomarker assays [6]. They discuss the challenges associated with defining targets appropriate for further biomarker assay development. Modern oncology has emerged to the era of molecular classification of cancer. In recent years, the identification of signaling pathways relevant to carcinogenesis has resulted in the development of a new generation of drugs. Cremona et al. conduct a signaling pathway analysis on patients with clear cell renal cell carcinomas (ccRCC) [7]. Unsupervised hierarchical clustering analysis significantly partitions the ccRCC samples into two major functional clusters: one is characterized by signaling pathways related to cell cycle and proliferation, the other by pathways related to cell death and survival. This type of analysis may be useful in selecting the best therapeutic approach for individual patients with ccRCC. Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Southern China and Southern Asia. It is usually diagnosed at advanced clinical stages, resulting in poor outcomes. There is an urgent need for diagnostic and predictive biomarkers to improve the outcomes of patients with NPC. Comparative proteomics has identified a large number of candidate biomarkers associated with NPC that may have potential applications in personalized and effective NPC management. Xiao et al. review the latest discovery and progress of proteomics-based biomarkers for early diagnosis and the prediction of metastasis, recurrence, prognosis and therapeutic response in NPC patients [8]. Transgelins are cytoskeletal proteins in the tumor microenvironment that are implicated in different aspects of cancer development. As a protein affecting the dynamics of the actin cytoskeleton, transgelin is both directly and indirectly involved in many cancer-related processes (such as tumor cell migration, invasion and epithelial-to-mesenchymal transition, cell signaling, proliferation, differentiation and apoptosis). Dvorakova et al. provide a comprehensive picture on transgelins [9]. They summarize contradictory observations on the tumor suppressor and protumorigenic roles of transgelin in both clinical and functional proteomics projects. There are nine glycosylated proteins approved as cancer biomarkers by the FDA, including a-fetoprotein in liver cancer, CA125 and human epididymis protein 4 in ovarian cancer, thyroglobulin in thyroid cancer, prostate-specific antigen in 132
prostate cancer, carcinoembryonic antigen in CRC, HER2/ NEU and CA15.3/CA27.29 in breast cancer [10]. Their diagnostic potential is based on the cancer-specific alterations of glycan structures on particular glycoproteins in blood. Badr et al. discuss some glycoproteome issues in cancer biomarker discovery, including a brief review of the nextgeneration technologies [11]. They particularly highlight the potential of several plant lectins as a unifying glycan-targeting affinity tool for the discovery of cancer glycobiomarkers. The identification of new druggable molecular targets and the development of new drug combinations lead to an increasing number of therapeutic options for cancer. One of the applications of cancer biomarker is to predict treatment outcome in terms of sensitivity and side effect. Skvortsov et al. review the molecular characteristics of cancer stem cells, which may provide additional possibilities to discover novel biomarkers to predict radiation resistance in cancer patients [12]. They also address some proteome-based findings that may be useful for further biomarker identification and preclinical and clinical validation. Multiple reaction monitoring (MRM) is a targeted MS approach for protein quantitation and it is emerging as a bridge for the gap between biomarker discovery and clinical validation. MRM assays are highly multiplexed and can verify many candidates simultaneously. This facilitates the development of biomarker panels with increased specificity. The development of scheduled MRM now enables hundreds of candidate biomarkers to be rapidly quantified and validated in a single MS analysis without the use of antibodies. Chambers et al. focus on the recent applications of MRM to the analysis of plasma and serum from cancer patients for biomarker verification [13]. They discuss the current status of this approach along with the future directions for targeted MS in clinical biomarker validation. Accurate cancer biomarkers are needed for early detection, disease classification, prediction of therapeutic response and monitoring treatment. Recent proteomics studies have discovered a large number of potential protein biomarkers. However, the lack of follow-up validation studies remains a major challenge in the translation of these candidate biomarkers into routine clinical setting. To translate the identified protein biomarkers into clinical use, fully developed tools and workflows with high robustness, sensitivity, specificity and throughput are needed. Nevertheless, the discovery of proteomic biomarkers is progressing at a tremendous pace. With better understanding of cancer biology and rapid development of more advanced proteomics technologies, some of these novel protein-based biomarkers will have considerable potential to translate into routine clinical practice. Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. Expert Rev. Proteomics 11(2), (2014)
Proteomics in translational cancer research
1.
Expert Review of Proteomics Downloaded from informahealthcare.com by National Taichung University of Science and Technology on 04/23/14 For personal use only.
2.
3.
4.
GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available from: http:// globocan.iarc.fr/Pages/fact_sheets_cancer. aspx Gupta S, Venkatesh A, Ray S, Srivastava S. Challenges and prospects for biomarker research: A current perspective from the developing world. Biochim Biophys Acta 2014;pii:S1570-9639(14)00002-8 Smith RA, Brooks D, Cokkinides V, et al. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J Clin 2013;63(2):88-105 Li D, Chan DW. Proteomic cancer biomarkers from discovery to approval: it’s
informahealthcare.com
in different aspects of cancer development. Expert Rev Proteomics 2014;11(2):149-65
worth the effort. Expert Rev Proteomics 2014;11(2):135-6
References 5.
Wang K, Huang C, Nice EC. Proteomics, genomics and transcriptomics: their emerging roles in the discovery and validation of colorectal cancer biomarkers. Expert Rev Proteomics 2014;11(2):179-205
6.
Drake RR, Kislinger T. The proteomics of prostate cancer exosomes. Expert Rev Proteomics 2014;11(2):167-77
7.
Foreword
10.
Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 2005;5(11): 845-56
11.
Badr HA, AlSadek DMM, Darwish AA, et al. Lectin approaches for glycoproteomics in FDA-approved cancer biomarkers. Expert Rev Proteomics 2014;11(2):227-36
Cremona M, Espina V, Caccia D, et al. Stratification of clear cell renal cell carcinoma by signaling pathway analysis. Expert Rev Proteomics 2014;11(2):237-49
12.
Skvortsov S, Debbage P, Cho WCS, et al. Putative biomarkers and therapeutic targets associated with radiation resistance. Expert Rev Proteomics 2014;11(2):207-14
8.
Xiao L, Xiao T, Wang Z-M, et al. Biomarker discovery of nasopharyngeal carcinoma by proteomics. Expert Rev Proteomics 2014;11(2):215-25
13.
9.
Dvorakova M, Nenutil R, Bouchal P. Transgelins, cytoskeletal proteins implicated
Chambers AG, Percy AJ, Simon R, Borchers CH. MRM for the verification of cancer biomarker proteins: recent applications to human plasma and serum. Expert Rev Proteomics 2014;11(2):137-48
133
SPECIAL FOCUS y Proteomics in translational cancer research
Foreword
Proteomics in translational cancer research: biomarker discovery for clinical applications Expert Rev. Proteomics 11(2), 131–133 (2014)
William CS Cho Department of Clinical Oncology, Health Authority, Hong Kong, China [email protected]
This special focus issue of Expert Review of Proteomics invites key opinion leaders to report their recent findings and views on the important topic of translating potential proteomic biomarkers to clinically useful, regulator-approved biomarkers: a challenging journey. The issue also highlights the difficulties associated with and the way forward in the discovery of proteomic cancer biomarkers for clinical applications, as well as presenting recent original research in the field.
Cancer is one of the most lethal diseases in the world; the estimated mortality is 8.2 million in 2012 [1]. The majority of deaths are due to a lack of early diagnosis and timely treatment. The discovery of cancer biomarkers for early detection and theragnosis is a possible solution to tackle this problem [2]. Early detection and accurate disease classification are key components of most cancer treatment programs and this drives the desire for more effective biomarkers [3]. However, quite a number of patients are diagnosed at advanced stage of cancer due to few sensitive and specific cancer biomarkers being available for clinical care. With the advantages of high sensitivity, specificity and throughput, the use of mass spectrometry (MS)-based proteomic analyses and their clinical applications have been increasingly recognized over the past decade. This technology is used in a wide range of biological and biomedical studies, including the analyses of cancer-specific post-translational modifications and cellular responses. Rapid advances in this high-throughput technology allow the identification of a large number of potential proteomic biomarkers, yet most of these discoveries have not been applied to routine clinical use. Challenges are often accompanied by opportunities. This special focus issue of Expert Review of Proteomics invites key opinion leaders to report their recent findings informahealthcare.com
10.1586/14789450.2014.899908
and views on this important topic, together with discussions of the difficulties associated with and the way forward in the discovery of proteomic cancer biomarkers for clinical applications. Li and Chan contribute an editorial with their expert opinions on why, despite the challenges faced, it is worth the effort to develop a discovered marker into a clinically validated diagnostic biomarker [4]. They comment on how the latest generation of proteomics technologies has allowed the discovery of many new biomarker candidates, but only a few are approved by the US FDA. As the potential rewards for improved cancer treatment are significant, they argue, it is worth the strenuous process to get there. Genomic and proteomic technologies can be used to measure molecular expressions at the transcript and protein levels to provide complementary information that paves the way for systems biology. It is a recent trend to integrate multiple disciplines for the development of panel biomarkers for cancer management. Wang et al. emphasize the merits of integrating proteomics and the emerging methylomic and miRNAomic strategies in the identification and validation of colorectal cancer (CRC) biomarkers [5]. They employ meta-analysis to provide a comprehensive list of previously reported CRCassociated proteins to facilitate further
2014 Informa UK Ltd
ISSN 1478-9450
131
Expert Review of Proteomics Downloaded from informahealthcare.com by National Taichung University of Science and Technology on 04/23/14 For personal use only.
Foreword
Cho
studies. These state-of-the-art systems biology approaches may lead to rapid advances in the discovery and validation of novel panel biomarkers for the early detection and surveillance of CRC. Exosomes secreted by prostate cancer can be isolated from prostatic secretions, seminal fluid, tissue, urine or blood for further proteomic analysis. Investigating the presence of prostatic acid phosphatase and prostate-specific antigen in prostate cancer exosomes, as well as the corresponding glycosylation and lipid profiles of the exosomes may provide a better understanding of the overall function of prostate cancer-derived exosomes in carcinogenesis and disease progression. Drake and Kislinger provide a summary of the ongoing efforts to characterize the proteome of unique prostate cancer-associated exosomes and their potential application in biomarker assays [6]. They discuss the challenges associated with defining targets appropriate for further biomarker assay development. Modern oncology has emerged to the era of molecular classification of cancer. In recent years, the identification of signaling pathways relevant to carcinogenesis has resulted in the development of a new generation of drugs. Cremona et al. conduct a signaling pathway analysis on patients with clear cell renal cell carcinomas (ccRCC) [7]. Unsupervised hierarchical clustering analysis significantly partitions the ccRCC samples into two major functional clusters: one is characterized by signaling pathways related to cell cycle and proliferation, the other by pathways related to cell death and survival. This type of analysis may be useful in selecting the best therapeutic approach for individual patients with ccRCC. Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Southern China and Southern Asia. It is usually diagnosed at advanced clinical stages, resulting in poor outcomes. There is an urgent need for diagnostic and predictive biomarkers to improve the outcomes of patients with NPC. Comparative proteomics has identified a large number of candidate biomarkers associated with NPC that may have potential applications in personalized and effective NPC management. Xiao et al. review the latest discovery and progress of proteomics-based biomarkers for early diagnosis and the prediction of metastasis, recurrence, prognosis and therapeutic response in NPC patients [8]. Transgelins are cytoskeletal proteins in the tumor microenvironment that are implicated in different aspects of cancer development. As a protein affecting the dynamics of the actin cytoskeleton, transgelin is both directly and indirectly involved in many cancer-related processes (such as tumor cell migration, invasion and epithelial-to-mesenchymal transition, cell signaling, proliferation, differentiation and apoptosis). Dvorakova et al. provide a comprehensive picture on transgelins [9]. They summarize contradictory observations on the tumor suppressor and protumorigenic roles of transgelin in both clinical and functional proteomics projects. There are nine glycosylated proteins approved as cancer biomarkers by the FDA, including a-fetoprotein in liver cancer, CA125 and human epididymis protein 4 in ovarian cancer, thyroglobulin in thyroid cancer, prostate-specific antigen in 132
prostate cancer, carcinoembryonic antigen in CRC, HER2/ NEU and CA15.3/CA27.29 in breast cancer [10]. Their diagnostic potential is based on the cancer-specific alterations of glycan structures on particular glycoproteins in blood. Badr et al. discuss some glycoproteome issues in cancer biomarker discovery, including a brief review of the nextgeneration technologies [11]. They particularly highlight the potential of several plant lectins as a unifying glycan-targeting affinity tool for the discovery of cancer glycobiomarkers. The identification of new druggable molecular targets and the development of new drug combinations lead to an increasing number of therapeutic options for cancer. One of the applications of cancer biomarker is to predict treatment outcome in terms of sensitivity and side effect. Skvortsov et al. review the molecular characteristics of cancer stem cells, which may provide additional possibilities to discover novel biomarkers to predict radiation resistance in cancer patients [12]. They also address some proteome-based findings that may be useful for further biomarker identification and preclinical and clinical validation. Multiple reaction monitoring (MRM) is a targeted MS approach for protein quantitation and it is emerging as a bridge for the gap between biomarker discovery and clinical validation. MRM assays are highly multiplexed and can verify many candidates simultaneously. This facilitates the development of biomarker panels with increased specificity. The development of scheduled MRM now enables hundreds of candidate biomarkers to be rapidly quantified and validated in a single MS analysis without the use of antibodies. Chambers et al. focus on the recent applications of MRM to the analysis of plasma and serum from cancer patients for biomarker verification [13]. They discuss the current status of this approach along with the future directions for targeted MS in clinical biomarker validation. Accurate cancer biomarkers are needed for early detection, disease classification, prediction of therapeutic response and monitoring treatment. Recent proteomics studies have discovered a large number of potential protein biomarkers. However, the lack of follow-up validation studies remains a major challenge in the translation of these candidate biomarkers into routine clinical setting. To translate the identified protein biomarkers into clinical use, fully developed tools and workflows with high robustness, sensitivity, specificity and throughput are needed. Nevertheless, the discovery of proteomic biomarkers is progressing at a tremendous pace. With better understanding of cancer biology and rapid development of more advanced proteomics technologies, some of these novel protein-based biomarkers will have considerable potential to translate into routine clinical practice. Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. Expert Rev. Proteomics 11(2), (2014)
Proteomics in translational cancer research
1.
Expert Review of Proteomics Downloaded from informahealthcare.com by National Taichung University of Science and Technology on 04/23/14 For personal use only.
2.
3.
4.
GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. Available from: http:// globocan.iarc.fr/Pages/fact_sheets_cancer. aspx Gupta S, Venkatesh A, Ray S, Srivastava S. Challenges and prospects for biomarker research: A current perspective from the developing world. Biochim Biophys Acta 2014;pii:S1570-9639(14)00002-8 Smith RA, Brooks D, Cokkinides V, et al. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J Clin 2013;63(2):88-105 Li D, Chan DW. Proteomic cancer biomarkers from discovery to approval: it’s
informahealthcare.com
in different aspects of cancer development. Expert Rev Proteomics 2014;11(2):149-65
worth the effort. Expert Rev Proteomics 2014;11(2):135-6
References 5.
Wang K, Huang C, Nice EC. Proteomics, genomics and transcriptomics: their emerging roles in the discovery and validation of colorectal cancer biomarkers. Expert Rev Proteomics 2014;11(2):179-205
6.
Drake RR, Kislinger T. The proteomics of prostate cancer exosomes. Expert Rev Proteomics 2014;11(2):167-77
7.
Foreword
10.
Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 2005;5(11): 845-56
11.
Badr HA, AlSadek DMM, Darwish AA, et al. Lectin approaches for glycoproteomics in FDA-approved cancer biomarkers. Expert Rev Proteomics 2014;11(2):227-36
Cremona M, Espina V, Caccia D, et al. Stratification of clear cell renal cell carcinoma by signaling pathway analysis. Expert Rev Proteomics 2014;11(2):237-49
12.
Skvortsov S, Debbage P, Cho WCS, et al. Putative biomarkers and therapeutic targets associated with radiation resistance. Expert Rev Proteomics 2014;11(2):207-14
8.
Xiao L, Xiao T, Wang Z-M, et al. Biomarker discovery of nasopharyngeal carcinoma by proteomics. Expert Rev Proteomics 2014;11(2):215-25
13.
9.
Dvorakova M, Nenutil R, Bouchal P. Transgelins, cytoskeletal proteins implicated
Chambers AG, Percy AJ, Simon R, Borchers CH. MRM for the verification of cancer biomarker proteins: recent applications to human plasma and serum. Expert Rev Proteomics 2014;11(2):137-48
133
