Biallelic inactivation of the tumor suppressor gene ? LKB1 has been detected in one third of sporadic lung adenocarcinomas (LACs), constituting a characteristic genetic signature of LACs. LKB1 has been reported to negatively regulate mammalian target of rapamycin (mTOR) signaling, thus, we hypothesize that mTOR is aberrantly activated in LACs or its premalignant lesions in which LKB1 is mutated and that inactivation of the mTOR pathway by rapamycin will prevent or suppress the development of these tumors. We propose to examine the role ofLKBl in lung tumorigenesis and identify potential new targets for chemopreventive therapy of LACs by generating a mouse model in which Lkbl is knocked out specifically in lung tissue.
Our specific aims are: 1) To generate a lung-specific Lkbl knockout mouse line based on the previously established Lkbl mouse model. 2) To examine the phenotype resulting from the disruption both Lkbl alleles in lung and analyze the mTOR status in these tumors. We hypothesize that the somatic inactivation of both Lkbl alleles in the lungs will result in a phenotype that mimics the sporadic character of human LACs or at the very minimum premalignant lesions. 3) To determine whether the mTOR inhibitor rapamycin can prevent or repress the onset of Lkbl -mutant LACs. Rapamycin and its analogues are currently being tested in clinical trials as novel anticancer agents, but the compounds have only shown activity in some patients. Our mouse model will be valuable in determining whether LKB1 status has any impact on rapamycin treatment of LACs. This information will be very useful to design a clinical trial of rapamycin analogs in patients with lung adenocarcinomas, taking their LKB1 status into account. Thus, the proposed studies will provide important information on the role of LKB1 in lung tumorigenesis and will provide a foundation for subsequent preclinical and clinical studies of the response and resistance of LACs to rapamycin therapy. ? ? ?
| Wei, Chongjuan; Amos, Christopher I; Zhang, Nianxiang et al. (2009) Chemopreventive efficacy of rapamycin on Peutz-Jeghers syndrome in a mouse model. Cancer Lett 277:149-54 |
| Wei, Chongjuan; Amos, Christopher I; Zhang, Nianxiang et al. (2008) Suppression of Peutz-Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin Cancer Res 14:1167-71 |
