BETHESDA, Md., April 1, 2007--Rapamycin, an FDA-approved drug normally used to help prevent the body from rejecting organ and bone marrow transplants and also used to coat cardiac stents, was highly effective in preventing the development of tobacco-related lung tumors in mice. In a study published in the April 1, 2007 issue of Clinical Cancer Research, researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, found that mice that were administered rapamycin one week after exposure to a very common tobacco-specific carcinogen showed a 90 percent decrease in the number of tumors, a 74 percent decrease in tumor size, and fewer abnormalities within their cancer cells. The scientists work also shows that mTOR, a protein targeted by rapamycin, plays a critical role in the early stages of development of certain lung tumors caused by tobacco exposure.
We estimate that there will be over 160,000 deaths from lung cancer this year, and 90 percent of those will be attributed to smoking. Quitting smoking reduces lung cancer risk by about 50 percent, said NCI Director John E. Niederhuber, M.D. By exploring methods of chemoprevention via agents such as rapamycin, we may be able to further reduce lung cancer risk.
Previous studies in mice have shown that nicotine and its metabolic byproduct, known as NNK, stimulate the activity of two proteins, Akt and mTOR, in normal cells that line the airways in the lungs. This activation makes the cells pre-cancerous. In addition, clinical studies have shown that Akt is activated in the majority of pre-cancerous lesions in smokers, and that Akt activation predicts shorter survival for non-small cell lung cancer patients, particularly for those in early stages or with small tumors. These studies suggested that Akt and mTOR are important elements in the formation and maintenance of tobacco-carcinogen induced lung tumors, and that targeting these proteins and the cellular pathway that they are associated with may be a realistic tactic for lung cancer chemoprevention. Because the most promising inhibitors of this pathway target mTOR as opposed to Akt, the researchers focused on an FDA-approved inhibitor of mTOR, rapamycin.
Investigators performed several experiments in mice to examine the effects of mTOR inhibition on new tumor formation and on established tumors. Mice were exposed to NNK (a carcinogen only found in tobacco) through injection into the peritoneum (the area that contains the abdominal organs). Rapamycin, which targets mTOR, was administered either one or 26 weeks after NNK administration. The group that was given rapamycin at week one was used to test the drug as a preventative agent. The group that received treatment at week 26 was used to test the effect on established tumors. A once daily dose given five out of seven days a week, which was a standard used in previous studies, was compared to an every-other-day, or ‘qod, regimen. Comparisons revealed that rapamycin levels were better maintained with an every-other-day administration.
Importantly, the levels of rapamycin achieved in mice were comparable to those in humans. On the daily regimen, which began on week 26, tumor size, the rate of tumor proliferation, and mTOR activity were reduced, but the rate at which tumor cells multiplied was unchanged. When rapamycin was administered one week after NNK, the every-other-day regimen was well tolerated and produced the best results in terms of tumor cell multiplication (90 percent reduction), cell abnormalities (changes in appearance, shape, etc.), and size (74 percent decrease). This was correlated with decreased proliferation of tumor cells and inhibition of mTOR.
Our studies provide an exciting link between exposure to an important tobacco carcinogen, NNK, and mTOR, said Phillip A. Dennis, M.D., Ph.D., head, Signal Transduction Section of NCI's Center for Cance r Research. The critical question is whether this approach would be safe and effective in smokers at high risk to develop lung cancer. Given that rapamycin is relatively inexpensive and FDA-approved for other indications, we are designing clinical trials in humans to address these questions and hope to have these answers in the near future.
Further research is needed to determine whether doses of rapamycin that achieve an anti-tumor effect in mice are similarly effective in humans, and whether giving a dose that would be sufficient for an anti-tumor effect would cause unacceptable levels of immune suppression or toxicity.
For more information on Dr. Denniss research, go to http://ccr.cancer.gov/Staff/Staff.asp?profileid=5727
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Reference: Granville C, Warfel N, Tsurutani J, Hollander C, Robertson M, Fox S, Veenstra T, Issaq H, Linnoila I, Dennis P. Identification of a highly effective rapamycin schedule that markedly reduces the size, multiplicity and phenotypic progression of tobacco carcinogen-induced murine lung tumors. C lin Cancer Res. Vol.13, No. 7.
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