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 preventslung 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 overexpressionof PGI2 synthase (PGIS) or chemoprevention with the PGI2 analog lloprost significantly reduced lung tumormultiplicity and incidence in mice, suggesting that manipulation of the arachidonic acid pathway downstreamfrom COX is a target for the prevention of lung cancer. These studies resulted in the initiation of achemoprevention trial in which patients at risk for lung cancer are treated with lloprost. Studies performedduring the previous funding period have shown that the anti-tumorigenic effects of PGI2 are not mediatedthrough the cell-surface receptor, but instead via activation of the peroxisome proliferator-activated receptorpathway, specifically PPAR^. Recent retrospective studies indicate that thiozolidinediones such asrosiglitazone, which are specific PPARy activators, reduce the risk of lung cancer. We have shown thatPPARy-transgenic mice are protected against lung tumorigenesis. In human NSCLC, PPARy activationinhibits anchorage-independent growth and invasiveness, and promotes differentiation. These effects areassociated with inhibition of COX-2 and decreases in cytokine production. While PGI2 and its analogsactivate PPARy in non-transformed epithelial cells, this ability is lost in many NSCLC lines. We have recentlydemonstrated that the inability of PGI2 to engage PPARy in NSCLC is correlated with the loss of signalingthrough Wnt7a and its cognate receptor Fzd9. The goal of the current proposal is to examine the role of PGI2and PPARy in the development of lung tumors. Studies will use in vitro studies and mouse models to definemolecular effectors and markers of response. These findings will be applied to analysis of human samplesfrom the lloprost trial and a new Rosiglitazone chemoprevention trial, as well as samples from human lungcancers.
Three specific aims are proposed.
Aim 1 will use in vitro approaches to define biomarkers oflloprost and Rosiglitazone sensitivity in a panel of NSCLC, and to examine interactions between theseagents and EGFR-TKIs.
Aim 2 will use a chemical carcinogenesis model to examine the combinatorialeffects of lloprost and rosiglitazone and erlotinib. Xenografts of human NSCLC will be used to establish theinteractions between lloprost and Fzd9.
Aim 3 will examine expression of molecules in this pathway insamples from chemoprevention trials and correlate changes with alterations in the degree of dysplasia andresponse to lloprost or Rosiglitazone. Expression of molecules in this pathway will be examined in humantumors using tissue microarrays. These studies will establish the role of this pathway in lung cancer initiationand progression, and help define new therapeutic targets.
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