Early changes in protein expression detected by mass spectrometry predict tumor response to molecular therapeutics

被引:104
作者
Reyzer, ML
Caldwell, RL
Dugger, TC
Forbes, JT
Ritter, CA
Guix, M
Arteaga, CL
Caprioli, RM
机构
[1] Vanderbilt Univ, Div Oncol, Sch Med, Vanderbilt Ingram Comprehens Canc Ctr, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Mass Spectrometry Res Ctr, Sch Med, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA
[4] Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA
[5] Vanderbilt Univ, Dept Canc Biol, Sch Med, Nashville, TN 37232 USA
[6] Ernst Moritz Arndt Univ Greifswald, Dept Pharmacol, Greifswald, Germany
[7] Ernst Moritz Arndt Univ Greifswald, Inst Pharm, Peter Holtz Res Ctr Pharmacol & Expt Therapeut, Greifswald, Germany
关键词
D O I
10.1158/0008-5472.CAN-04-2231
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 beta4 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.
引用
收藏
页码:9093 / 9100
页数:8
相关论文
共 34 条
[1]   Trastuzumab, an appropriate first-line single-agent therapy for HER2-overexpressing metastatic breast cancer [J].
Arteaga, CL .
BREAST CANCER RESEARCH, 2003, 5 (02) :96-100
[2]   Studies of the potential utility of Ki67 as a predictive molecular marker of clinical response in primary breast cancer [J].
Assersohn, L ;
Salter, J ;
Powles, TJ ;
A'hern, R ;
Makris, A ;
Gregory, RK ;
Chang, J ;
Dowsett, M .
BREAST CANCER RESEARCH AND TREATMENT, 2003, 82 (02) :113-123
[3]  
Bukholm IK, 1998, J PATHOL, V185, P262, DOI 10.1002/(SICI)1096-9896(199807)185:3<262::AID-PATH97>3.0.CO
[4]  
2-Y
[5]   HUMANIZATION OF AN ANTI-P185HER2 ANTIBODY FOR HUMAN CANCER-THERAPY [J].
CARTER, P ;
PRESTA, L ;
GORMAN, CM ;
RIDGWAY, JBB ;
HENNER, D ;
WONG, WLT ;
ROWLAND, AM ;
KOTTS, C ;
CARVER, ME ;
SHEPARD, HM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (10) :4285-4289
[6]   Role of thymosin β4 in tumor metastasis and angiogenesis [J].
Cha, HJ ;
Jeong, MJ ;
Kleinman, HK .
JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2003, 95 (22) :1674-1680
[7]  
Chang JC, 2003, BREAST CANCER RES TR, V82, pS13
[8]   Profiling and imaging proteins in the mouse epididymis by imaging mass spectrometry [J].
Chaurand, P ;
Fouchécourt, S ;
DaGue, BB ;
Xu, BGJ ;
Reyzer, ML ;
Orgebin-Crist, MC ;
Caprioli, RM .
PROTEOMICS, 2003, 3 (11) :2221-2239
[9]  
Chaurand P, 2001, PROTEOMICS, V1, P1320, DOI 10.1002/1615-9861(200110)1:10<1320::AID-PROT1320>3.0.CO
[10]  
2-G