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Early Changes in Protein Expression Detected by Mass Spectrometry Predict Tumor Response to Molecular Therapeutics

¹ Mass Spectrometry Research Center, Departments of ² Biochemistry, ³ Medicine, and ⁴ Cancer Biology, ⁵ Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and ⁶ Department of Pharmacology and Institute of Pharmacy, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt-Universitat Greifswald, Greifswald, Germany

Biomarkers that predict therapeutic response are essential for the development of anticancer therapies. We have used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to directly analyze protein profiles in mouse mammary tumor virus/HER2 transgenic mouse frozen tumor sections after treatment with the erbB receptor inhibitors OSI-774 and Herceptin. Inhibition of tumor cell proliferation and induction of apoptosis and tumor reduction were predicted by a >80% reduction in thymosin ß4 and ubiquitin levels that were detectable after 16 hours of a single drug dose before any evidence of in situ cellular activity. These effects were time- and dose-dependent, and their spatial distribution in the tumor correlated with that of the small-molecule inhibitor OSI-774. In addition, they predicted for therapeutic synergy of OSI-774 and Herceptin as well as for drug resistance. These results suggest that drug-induced early proteomic changes as measured by MALDI-MS can be used to predict the therapeutic response to established and novel therapies.

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