Prostacyclin and Peroxisome Proliferator- Activated Receptor Gamma in Lung Cancer

类二十烷酸产生的增加与包括肺癌在内的许多类型的癌症有关。 抑制环加氧酶（考克斯，PGH 2合酶）活性可减少类二十烷酸的产生并防止 肺癌动物模型前列环素I2（PGI 2）是PGH 2代谢物，具有抗炎、抗增殖、 和有效的抗转移特性。我们的实验室已经证明， PGI 2合成酶（PGIS）或PGI 2类似物伊洛前列素的化学预防显著降低了肺肿瘤 在小鼠中的多重性和发病率，表明操纵花生四烯酸途径下游 从考克斯是一个目标，为预防肺癌。这些研究导致了 在一项化学预防试验中，有肺癌风险的患者接受了伊洛前列素治疗。进行的研究 在上一个资助期间，已经表明PGI 2的抗肿瘤作用不是介导的， 通过细胞表面受体，而是通过激活过氧化物酶体增殖物激活受体 途径，特别是PPAR γ。最近的回顾性研究表明，噻唑烷二酮类，如 罗格列酮是特异性PPARy激活剂，可降低肺癌风险。我们已经证明 PPARy转基因小鼠被保护免于肺肿瘤发生。在人NSCLC中， 抑制锚定非依赖性生长和侵袭，并促进分化。这些影响是 与考克斯-2的抑制和细胞因子产生的减少有关。而PGI 2及其类似物 虽然在非转化上皮细胞中激活PPARy，但这种能力在许多NSCLC细胞系中丧失。我们最近 证实了PGI 2不能与NSCLC中的PPARy结合与信号转导的丧失相关， 通过Wnt 7a及其同源受体Fzd 9。当前提案的目标是检查PGI 2的作用 和PPARy在肺肿瘤发展中的作用。研究将使用体外研究和小鼠模型来定义 分子效应物和反应标记物。这些发现将应用于人体样本的分析 来自伊洛前列素试验和一项新的罗格列酮化学预防试验，以及来自人肺的样本 癌的提出了三个具体目标。目标1将使用体外方法来定义 一组NSCLC患者中的洛前列素和罗格列酮敏感性，并检查这些药物之间的相互作用 药物和EGFR-TKI。目的2将使用化学致癌模型来检查组合 洛前列素、罗格列酮和厄洛替尼的作用。将使用人NSCLC的异种移植物来建立 伊洛前列素和Fzd 9之间的相互作用。Aim 3将检查在这一途径中的分子表达， 来自化学预防试验的样本，并将变化与异型增生程度的改变相关联， 对伊洛前列素或罗格列酮的反应。将在人类中检测该途径中分子的表达。 使用组织微阵列的肿瘤。这些研究将确立该通路在肺癌发生中的作用 并帮助确定新的治疗靶点。

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.