Inhibition of Mammalian Target of Rapamycin by Rapamycin Causes the Regression of Carcinogen-induced Skin Tumor Lesions

被引:57
作者
Amornphimoltham, Panomwat [1 ]
Leelahavanichkul, Kantima [1 ]
Molinolo, Alfredo [1 ]
Patel, Vyomesh [1 ]
Gutkind, J. Silvio [1 ]
机构
[1] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Res, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1158/1078-0432.CCR-08-0703
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The activation of Akt/mammalian target of rapamycin (mTOR) pathway represents a frequent event in squamous cell carcinoma (SCC) progression, thus raising the possibility of using specific mTOR inhibitors for the treatment of SCC patients. In this regard, blockade of mTOR with rapamycin prevents the growth of human head and neck SCC cells when xenotransplanted into immunodeficient mice. However, therapeutic responses in xenograft tumors are not always predictive of clinical anticancer activity. Experimental Design: As genetically defined and chemically induced animal cancer models often reflect better the complexity of the clinical setting, we used here a two-step chemical carcinogenesis model to explore the effectiveness of rapamycin for the treatment of skin SCC. Results: Rapamycin exerted a remarkable anticancer activity in this chemically induced cancer model, decreasing the tumor burden of mice harboring early and advanced tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumor biopsies and clustering analysis revealed that rapamycin causes the rapid decrease in the phosphorylation status of mTOR targets followed by the apoptotic death of cancer cells and the reduction in the growth and metabolic activity of the surviving ones, concomitant with a decrease in the population of cancer cells expressing mutant p53. This approach enabled investigating the relationship among molecular changes caused by mTOR inhibition, thus helping identify relevant biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical setting. Conclusions: Together, these findings provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular targeted approach to treat SCC.
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收藏
页码:8094 / 8101
页数:8
相关论文
共 29 条
[1]  
Affara NI, 2006, ANTICANCER RES, V26, P2805
[2]   Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck [J].
Amornphimoltham, P ;
Patel, V ;
Sodhi, A ;
Nikitakis, NG ;
Sauk, JJ ;
Sausville, EA ;
Molinolo, AA ;
Gutkind, JS .
CANCER RESEARCH, 2005, 65 (21) :9953-9961
[3]   Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01 [J].
Amornphimoltham, P ;
Sriuranpong, V ;
Patel, V ;
Benavides, F ;
Conti, CJ ;
Sauk, J ;
Sausville, EA ;
Molinolo, AA ;
Gutkind, JS .
CLINICAL CANCER RESEARCH, 2004, 10 (12) :4029-4037
[4]   MOUSE SKIN CARCINOMAS INDUCED INVIVO BY CHEMICAL CARCINOGENS HAVE A TRANSFORMING HARVEY-RAS ONCOGENE [J].
BALMAIN, A ;
PRAGNELL, IB .
NATURE, 1983, 303 (5912) :72-74
[5]   Genetically engineered models have advantages over xenografts for preclinical studies [J].
Becher, OJ ;
Holland, EC .
CANCER RESEARCH, 2006, 66 (07) :3355-3358
[6]   Immunophenotypic analysis of inflammatory breast cancers: identification of an 'inflammatory signature' [J].
Charafe-Jaufrret, E ;
Tarpin, C ;
Bardou, VJ ;
Bertucci, FO ;
Ginestier, C ;
Braud, AC ;
Puig, B ;
Geneix, J ;
Hassoun, J ;
Birnbaum, D ;
Jacquemier, J ;
Viens, P .
JOURNAL OF PATHOLOGY, 2004, 202 (03) :265-273
[7]   MULTISTAGE CARCINOGENESIS IN MOUSE SKIN [J].
DIGIOVANNI, J .
PHARMACOLOGY & THERAPEUTICS, 1992, 54 (01) :63-128
[8]   G-protein-coupled receptors and cancer [J].
Dorsam, Robert T. ;
Gutkind, J. Silvio .
NATURE REVIEWS CANCER, 2007, 7 (02) :79-94
[9]   Medical progress - Head and neck cancer [J].
Forastiere, A ;
Koch, W ;
Trotti, A ;
Sidransky, D .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (26) :1890-1900
[10]   Maximizing mouse cancer models [J].
Frese, Kristopher K. ;
Tuveson, David A. .
NATURE REVIEWS CANCER, 2007, 7 (09) :645-658