CHEMICAL BIOLOGY AND CHEMOPROTEOMICS FOR DRUG SAFETY
Reactive electrophiles produced by metabolism of drugs and by oxidation of endogenous lipids covalently modify proteins and these reactions drive adaptive and toxic responses. Dr. Liebler’s program led the application of mass spectrometry to identify, map and quantify electrophile and oxidant modifications, thereby providing a discrete mechanistic basis to develop and test hypotheses regarding covalent and oxidative protein modifications.
The Liebler team reported the first global analyses of protein electrophile targets in cells, the first site-specific mapping of adducts and S-sulfenyl redox modifications across proteomes and described the relationship of protein functional ontology, damage and toxicity. Most recently, this work was extended to map and quantify the off-target covalent protein binding of carfilzomib, a covalent proteasome inhibitor drug. This study provides a roadmap for evaluation of the on/off target binding of new generation covalent protein-modifying therapeutics.
Yang, J., Tallman, K. A., Porter, N. A., and Liebler, D. C. (2015)
Quantitative chemoproteomics for site-specific analysis of protein alkylation by 4-hydroxy-2-nonenal in cells.
Anal Chem 87, 2535-2541
Yang, J., Gupta, V., Carroll, K. S., and Liebler, D. C. (2014)
Site-specific mapping and quantification of protein S-sulphenylation in cells.
Nat Commun 5, 4776
Codreanu, S. G., Ullery, J. C., Zhu, J., Tallman, K. A., Beavers, W. N., Porter, N. A., Marnett, L. J., Zhang, B., and Liebler, D. C. (2014)
Alkylation damage by lipid electrophiles targets functional protein systems.
Mol Cell Proteomics 13, 849-859
Federspiel, J. D., Codreanu, S. G., Goyal, S., Albertolle, M. E., Lowe, E., Teague, J., Wong, H., Guengerich, F. P., and Liebler, D. C. (2016)
Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells.
Mol Cell Proteomics 15, 3233-3242
Federspiel, J. D., Codreanu, S. G., Palubinsky, A. M., Winland, A. J., Betanzos, C. M., McLaughlin, B., and Liebler, D. C. (2016)
Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress.
Mol Cell Proteomics 15, 1947-1961
PROTEOMIC TECHNOLOGIES AND PROTEOGENOMIC ANALYSIS OF CANCER
Dr. Liebler and his colleagues, through the Ayers Institute at Vanderbilt and through the NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) network has led the development, evaluation and standardization of MS proteomics platforms to application in translational research and clinical diagnostics. The Liebler group and CPTAC collaborators were the first to integrate proteomics and genomics to trace the path from genomic alterations through proteins to cancer phenotypes. Their 2014 study in Nature of colon and rectal tumors was the first proteogenomic analysis of a human cancer. The Liebler group also led the development of multiplexed MS assays to quantify proteins in functional systems that control cancer phenotypes, including a 75 protein assay panel for proteins in central carbon metabolism and an 80 protein assay panel for protein tyrosine kinases.
Kim, H. J., Lin, D., Lee, H. J., Li, M., and Liebler, D. C. (2016)
Quantitative Profiling of Protein Tyrosine Kinases in Human Cancer Cell Lines by Multiplexed Parallel Reaction Monitoring Assays.
Mol Cell Proteomics 15, 682-691
Hutton, J. E., Wang, X., Zimmerman, L. J., Slebos, R. J., Trenary, I. A., Young, J. D., Li, M., and Liebler, D. C. (2016)
Oncogenic KRAS and BRAF Drive Metabolic Reprogramming in Colorectal Cancer.
Mol Cell Proteomics 15, 2924-2938
Zhang, B., Wang, J., Wang, X., Zhu, J., Liu, Q., Shi, Z., Chambers, M. C., Zimmerman, L. J., Shaddox, K. F., Kim, S., Davies, S. R., Wang, S., Wang, P., Kinsinger, C. R., Rivers, R. C., Rodriguez, H., Townsend, R. R., Ellis, M. J., Carr, S. A., Tabb, D. L., Coffey, R. J., Slebos, R. J., Liebler, D. C., and Nci, C. (2014)
Proteogenomic characterization of human colon and rectal cancer.
Nature 513, 382-387
Halvey, P. J., Wang, X., Wang, J., Bhat, A. A., Dhawan, P., Li, M., Zhang, B., Liebler, D. C., and Slebos, R. J. (2014)
Proteogenomic analysis reveals unanticipated adaptations of colorectal tumor cells to deficiencies in DNA mismatch repair.
Cancer Res 74, 387-397
Sprung, R. W., Martinez, M. A., Carpenter, K. L., Ham, A. J., Washington, M. K., Arteaga, C. L., Sanders, M. E., and Liebler, D. C. (2012)
Precision of multiple reaction monitoring mass spectrometry analysis of formalin-fixed, paraffin-embedded tissue.
J Proteome Res 11, 3498-3505
QUANTITATIVE ANALYSIS OF IMMUNE CHECKPOINT PROTEINS
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. The Liebler group recently developed targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), programmed cell death 1 ligand 2 (PD-L2) and other immune checkpoint proteins at fmol/microgram protein levels in formalin fixed, paraffin-embedded tissue sections. These analyses also enables quantification of post-translationally modified forms of these proteins, which may affect their physiologic interactions and responses to drugs. These measurements enable quantitative comparisons of multiple key regulators of the immune-tumor interface. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics.
Morales-Betanzos, C.A., Lee, H., Gonzalez Ericsson, P.I., Balko, J.M., Johnson, D.B., Zimmerman, L.J. and Liebler, D.C. (2017)
Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma.
Mol Cell Proteomics pii: mcp.000037.2017
DANIEL C. LIEBLER
FOUNDER AND PRESIDENT
Daniel C. Liebler is President and Founder of Protypia, LLC and Adjunct Professor of Biochemistry at the Vanderbilt University School of Medicine. Dr. Liebler’s research program has focused for 30 years on the application of analytical technology, particularly mass spectrometry, to study the interactions of chemicals with biological systems. His group has made important contributions to the fields of antioxidant chemistry, toxicology mechanisms, proteomics, chemical biology and cancer proteogenomics. Dr. Liebler has authored 295 peer reviewed publications.
Prior to forming Protypia, Dr. Liebler was Professor of Biochemistry, Pharmacology and Biomedical Informatics at Vanderbilt (2003-2016). Dr. Liebler served on the faculty of the Department of Pharmacology and Toxicology in the College of Pharmacy at the University of Arizona (1987-2003). At Arizona, he served as Director of the Southwest Environmental Health Sciences Center and the Toxicology Training Program.
Dr. Liebler received a B.S. in Chemistry from Villanova University and a Ph.D. in Pharmacology from Vanderbilt, where he trained in the laboratory of F. Peter Guengerich. He did postdoctoral training in the laboratory of Donald J. Reed at Oregon State University. He was elected Fellow of the American Association for the Advancement of Science in 2008 and was elected Fellow of the American Chemical Society in 2013.
Dr. Liebler is a member of the Expert Panel for the Cosmetic Ingredient review, which evaluates the safety of chemical ingredients used in cosmetics in the United States. He is also a member of the Expert Panel for Fragrance Safety for the Research Institute for Fragrance Materials. Dr. Liebler contributes expertise on chemical and toxicologic aspects of safety evaluation and risk assessment, with an emphasis on inference between structurally related chemicals to enable optimal use of safety data.
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