To test the hypothesis that inhibition of the Akt/mammalian target of rapamycin (mTOR) pathway can prevent tobacco-carcinogen induced murine lung tumors, several studies were completed using the A/J mouse model and rapamycin, a Food and Drug Administration (FDA)-approved inhibitor of mTOR. Tumors were induced by intraperitoneal injection of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Treatment of established NNK-induced tumors decreased tumor size, which was associated with decreased tumor cell proliferation and inhibition of mTOR in tumors and surrogate tissues. Short-term administration of rapamycin prior to the development of tumors inhibited mTOR in lung and surrogate tissue, and was associated with a trend toward a decrease in tumor number. However, mice that were treated with continuous rapamycin developed 90% fewer tumors, and the tumors that did develop were significantly smaller. mTOR was inhibited in surrogate tissues and in tumors arising in the presence of rapamycin. Under these conditions, rapamycin modestly impacted T cell function, and a reciprocal relationship between NNK and rapamycin on the infiltration of Forkhead box p3 (Foxp3)-expressing cells to the lung was observed. Finally, microarray analysis of tumors arising in the presence and absence of rapamycin revealed genes that differentiated between these sets of tumors, including 3 genes involved in circadian rhythm signaling, and the putative tumor suppressor methyl binding domain (Mbd)-1. Overall, these studies suggest that mTOR inhibition is a viable approach to preventing tobacco-carcinogen induced tumor formation with limited toxicity, and provide a basis for testing the safety of mTOR inhibitors for use in humans at high risk to develop lung cancer. In addition, the identification of Foxp3-expressing cells in NNK-induced tumor formation and the discovery of gene expression profiles associated with rapamycin administration provide the basis for studying the utility of these genes and/or proteins as biomarkers for rapamycin administration.
|Advisor:||Dennis, Phillip A.|
|Commitee:||Ceryak, Susan M., Colburn, Nancy H., Kennedy, Katherine A., Leitenberg, David, Patierno, Steven R.|
|School:||The George Washington University|
|Department:||Biochemistry and Molecular Genetics|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 69/02, Dissertation Abstracts International|
|Keywords:||Chemoprevention, Lung cancer, Rapamycin, Tobacco, Tumorigenesis, mTOR|
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