A77

Human and murine pre-neoplastic lung lesions induced by tobacco exposure are characterized by increased activation of the kinases Akt and mTOR, suggesting that activation of this pathway is important for the development of lung cancer. To test this hypothesis, we administered rapamycin, an inhibitor of mTOR, to A/J mice that had been exposed to the tobacco carcinogen, NNK. When rapamycin was given on a daily 5 of 7 day regimen, mTOR activity was inhibited. Tumor size but not multiplicity was reduced. To optimize rapamycin delivery, the pharmacokinetics and pharmacodynamics of a daily 5/7 regimen were compared to an every-other-day regimen. Immunohistochemical analysis of S6 phosphorylation in lung tissue from this study revealed that although mTOR was inhibited equally immediately after rapamycin delivery, recovery of mTOR activity was different with the two regimens. With the daily 5/7 regimen, mTOR activity completely recovered after the 72 hour rest-period, which corresponded to blood levels of rapamycin that were undetectable. With every-other-day rapamycin, recovery of S6 phosphorylation was incomplete after the washout period, and rapamycin levels in this group nadired at 16.4 ng/ml, which is comparable to levels reached in humans. These studies suggested that an every-other-day regimen might be more effective than a daily 5/7 regimen. To test this, every-other-day rapamycin (1.5 mg/kg) was administered one week after NNK exposure, prior to tumor development. Rapamycin was continued for 12 wk and was well tolerated. At 16 wk, rapamycin reduced the multiplicity of tobacco-carcinogen induced tumors by 90%. Tumors that did develop showed decreased phenotypic progression and size that was associated with a decreased rate of proliferation. Inhibition of tumorigenesis by rapamycin was associated with mTOR inhibition in lung tumors, lung tissues, and surrogate tissues. These studies identify a highly effective treatment schedule of rapamycin that markedly reduced the burden of tobacco carcinogen-induced lung tumors. Given the FDA-approval of rapamycin to prevent rejection of kidney transplants and the broad clinical experience with rapamycin, these studies provide a strong rationale to pursue prevention trials with rapamycin in smokers at high risk to develop lung cancer.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]