Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by gastrointestinal hamartomatous polyps. Patients with PJS are at higher risk for developing various types of cancer. Germline mutations of the tumor suppressor gene LKB1 are responsible for most PJS cases. To date, therapy for PJS has been limited to surgically resecting of clinically significant polyps. LKB1 has been shown to negatively regulate the mammalian target of rapamycin (mTOR) via AMP-activated protein kinase activation of the TSC2 tumor suppressor. Hyperactivation of mTOR signaling in PJS suggests that mTOR inhibitors could be used to prevent and treat polyposis. We generated an Lkb1 mouse model of PJS that develop severe gastrointestinal polyposis. Our pilot trials revealed that rapamcyin efficaciously inhibited PJ polyposis in Lkb1 mice;this finding strengthens the rationale for using mTOR as a therapeutic target for PJS. However, rapamycin, is not an ideal agent because it irreversibly inhibit mTOR signaling, thereby complicating the control of the drug's side effects. Recently, niclosamide, an established anthelminthic drug, was reported to be a novel inhibitor of mTOR signaling, with desirable pharmacologic features. Therefore, in the proposed study, we will determine whether niclosamide can be used to prevent and treat PJS polyposis in Lkb1 mice. In brief, we will treat Lkb1 mice with niclosamide before and after the onset of polyposis. During the course of niclosamide treatment, mice will be examined biweekly with Magnetic Resonance Imaging (MRI) to monitor changes in polyps size. We will also use reverse phase protein arrays (RPPA), a high- throughput, functional proteomic technique to evaluate the antitumor effect of niclosamide at the protein level. The findings of this proposed study will have important implications for the future use of niclosamide in preventing and suppressing PJS polyposis and PJS-associated cancer. In addition, because the mTOR pathway is activated in most common cancer, identifying effective chemopreventive agents for PJS and PJS-associated cancer may have broader translational potential for the prevention and treatment of other cancer with dysregulated mTOR signaling. Given that the mTOR pathway is aberrantly activated in most common cancer, the long-term goal of our overall study is to establish our PJS mouse model as an intervention model that can be used to identify effective chemopreventive agents for PJS, PJS-associated cancer, and all other common cancer with dysregulated mTOR signaling.
The findings resulting from the proposed study will provide important information about the chemoprevention of PJS polyposis and PJS-associated cancer by targeting mTOR signaling. Given that the mTOR pathway is aberrantly activated in most common cancers, such findings will facilitate the prevention of other common cancers with dysregulated mTOR signaling.
|Huang, Yu-Jing; Frazier, Marsha L; Zhang, Nianxiang et al. (2014) Reverse-phase protein array analysis to identify biomarker proteins in human pancreatic cancer. Dig Dis Sci 59:968-75|