TY - JOUR
T1 - Using reverse-phase protein arrays as pharmacodynamic assays for functional proteomics, biomarker discovery, and drug development in cancer
AU - Lu, Yiling
AU - Ling, Shiyun
AU - Hegde, Apurva M.
AU - Byers, Lauren A.
AU - Coombes, Kevin
AU - Mills, Gordon B.
AU - Akbani, Rehan
N1 - Funding Information:
This work was supported in part by the US National Institutes of Health/National Cancer Institute (NIH/NCI) through the Cancer Center Support Grant (NCI P30CA016672, Bioinformatics Shared Resource); the MD Anderson TCGA Genome Data Analysis Center grant (NCI CA143883 and CA083639); the Ovary SPORE (NCI P50CA083639); the Endometrial SPORE (NCI P50CA098258); ICBP (NCI U54CA112970); LNCS (NCI U54HG008100); the Cancer Prevention Research Institute of Texas grant (CPRIT RP130397); the Adelson Medical Research Foundation; the Mary K. Chapman Foundation; and the Michael & Susan Dell Foundation (honoring Lorraine Dell). Research performed at The University of Texas MD Anderson Cancer Center.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents. Understanding these mechanisms is necessary to identify patients likely to benefit from treatment and to develop rational drug combinations to prevent or bypass therapeutic resistance. There is an urgent need for a robust approach to assess protein levels and protein function in model systems and across patient samples. While “shot gun” mass spectrometry can provide in-depth analysis of proteins across a limited number of samples, and emerging approaches such as multiple reaction monitoring have the potential to analyze candidate markers, mass spectrometry has not entered into general use because of the high cost, requirement of extensive analysis and support, and relatively large amount of material needed for analysis. Rather, antibody-based technologies, including immunohistochemistry, radioimmunoassays, enzyme-linked immunosorbent assays (ELISAs), and more recently protein arrays, remain the most common approaches for multiplexed protein analysis. Reverse-phase protein array (RPPA) technology has emerged as a robust, sensitive, cost-effective approach to the analysis of large numbers of samples for quantitative assessment of key members of functional pathways that are affected by tumor-targeting therapeutics. The RPPA platform is a powerful approach for identifying and validating targets, classifying tumor subsets, assessing pharmacodynamics, and identifying prognostic and predictive markers, adaptive responses and rational drug combinations in model systems and patient samples. Its greatest utility has been realized through integration with other analytic platforms such as DNA sequencing, transcriptional profiling, epigenomics, mass spectrometry, and metabolomics. The power of the technology is becoming apparent through its use in pathology laboratories and integration into trial design and implementation.
AB - The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents. Understanding these mechanisms is necessary to identify patients likely to benefit from treatment and to develop rational drug combinations to prevent or bypass therapeutic resistance. There is an urgent need for a robust approach to assess protein levels and protein function in model systems and across patient samples. While “shot gun” mass spectrometry can provide in-depth analysis of proteins across a limited number of samples, and emerging approaches such as multiple reaction monitoring have the potential to analyze candidate markers, mass spectrometry has not entered into general use because of the high cost, requirement of extensive analysis and support, and relatively large amount of material needed for analysis. Rather, antibody-based technologies, including immunohistochemistry, radioimmunoassays, enzyme-linked immunosorbent assays (ELISAs), and more recently protein arrays, remain the most common approaches for multiplexed protein analysis. Reverse-phase protein array (RPPA) technology has emerged as a robust, sensitive, cost-effective approach to the analysis of large numbers of samples for quantitative assessment of key members of functional pathways that are affected by tumor-targeting therapeutics. The RPPA platform is a powerful approach for identifying and validating targets, classifying tumor subsets, assessing pharmacodynamics, and identifying prognostic and predictive markers, adaptive responses and rational drug combinations in model systems and patient samples. Its greatest utility has been realized through integration with other analytic platforms such as DNA sequencing, transcriptional profiling, epigenomics, mass spectrometry, and metabolomics. The power of the technology is becoming apparent through its use in pathology laboratories and integration into trial design and implementation.
KW - Biomarker
KW - Drug development
KW - Pharmacodynamic
KW - Proteomics
KW - RPPA
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U2 - 10.1053/j.seminoncol.2016.06.005
DO - 10.1053/j.seminoncol.2016.06.005
M3 - Review article
C2 - 27663479
AN - SCOPUS:84990219126
SN - 0093-7754
VL - 43
SP - 476
EP - 483
JO - Seminars in Oncology
JF - Seminars in Oncology
IS - 4
ER -