Increased eicosanoid production has been associated with many types of cancer including lung cancer. Inhibition of cyclooxygenase (COX, PGH2 synthase) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostacyclin I2 (PGI2) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and potent anti-metastatic properties. Our laboratory has shown that targeted overexpression of PGI2 synthase (PGIS) or chemoprevention with the PGI2 analog lloprost significantly reduced lung tumor multiplicity and incidence in mice, suggesting that manipulation of the arachidonic acid pathway downstream from COX is a target for the prevention of lung cancer. These studies resulted in the initiation of a chemoprevention trial in which patients at risk for lung cancer are treated with lloprost. Studies performed during the previous funding period have shown that the anti-tumorigenic effects of PGI2 are not mediated through the cell-surface receptor, but instead via activation of the peroxisome proliferator-activated receptor pathway, specifically PPAR^. Recent retrospective studies indicate that thiozolidinediones such as rosiglitazone, which are specific PPARy activators, reduce the risk of lung cancer. We have shown that PPARy-transgenic mice are protected against lung tumorigenesis. In human NSCLC, PPARy activation inhibits anchorage-independent growth and invasiveness, and promotes differentiation. These effects are associated with inhibition of COX-2 and decreases in cytokine production. While PGI2 and its analogs activate PPARy in non-transformed epithelial cells, this ability is lost in many NSCLC lines. We have recently demonstrated that the inability of PGI2 to engage PPARy in NSCLC is correlated with the loss of signaling through Wnt7a and its cognate receptor Fzd9. The goal of the current proposal is to examine the role of PGI2 and PPARy in the development of lung tumors. Studies will use in vitro studies and mouse models to define molecular effectors and markers of response. These findings will be applied to analysis of human samples from the lloprost trial and a new Rosiglitazone chemoprevention trial, as well as samples from human lung cancers.
Three specific aims are proposed.
Aim 1 will use in vitro approaches to define biomarkers of lloprost and Rosiglitazone sensitivity in a panel of NSCLC, and to examine interactions between these agents and EGFR-TKIs.
Aim 2 will use a chemical carcinogenesis model to examine the combinatorial effects of lloprost and rosiglitazone and erlotinib. Xenografts of human NSCLC will be used to establish the interactions between lloprost and Fzd9.
Aim 3 will examine expression of molecules in this pathway in samples from chemoprevention trials and correlate changes with alterations in the degree of dysplasia and response to lloprost or Rosiglitazone. Expression of molecules in this pathway will be examined in human tumors using tissue microarrays. These studies will establish the role of this pathway in lung cancer initiation and progression, and help define new therapeutic targets.
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