Prostacyclin and Peroxisome Proliferator- Activated Receptor Gamma in Lung Cancer

二十烷类化合物的产生增加与许多类型的癌症有关，包括肺癌。 抑制环氧合酶(COX、PGH2合成酶)活性减少二十烷类化合物的产生并防止 在动物模型中发现肺癌。前列环素I2(PGI2)是一种前列环素(PGH2)的代谢物，具有抗炎、抗增殖、 和强大的抗转移特性。我们的实验室已经证明了靶向过度表达 前列腺素I2合成酶(PGIs)或前列腺素I2类似物洛前列素的化学预防显著减少肺癌 在小鼠中的多发性和发病率，表明对花生四烯酸途径下游的操纵 从COX来看是预防肺癌的靶点。这些研究导致启动了一项 有肺癌风险的患者接受伊洛前列素治疗的化学预防试验。进行的研究 在之前的资助期间，已经表明PGI2的抗肿瘤作用不是通过中介的 通过细胞表面受体，而不是通过激活过氧化物酶体增殖物激活的受体 途径，特别是PPAR^。最近的回顾性研究表明，硫唑烷二酮类化合物 罗格列酮是一种特异性的PPARy激活剂，可以降低肺癌的风险。我们已经证明了 PPARy转基因小鼠可以预防肺部肿瘤的发生。在人类非小细胞肺癌中，PPARy激活 抑制非锚定生长和侵袭性，促进分化。这些影响是 与COX-2的抑制和细胞因子的产生减少有关。而PGI2及其类似物 在未转化的上皮细胞中激活PPARy，这一能力在许多非小细胞肺癌株中缺失。我们最近做了 证明在非小细胞肺癌中，PGI2不能参与PPARy与信号的丢失有关 通过Wnt7a及其同源受体Fzd9。当前提案的目标是研究PGI2的作用 PPARy在肺癌发生发展中的作用。研究将使用体外研究和小鼠模型来确定 反应的分子效应物和标志物。这些发现将应用于人体样本的分析 来自lloprost试验和一项新的罗格列酮化学预防试验，以及来自人类肺部的样本 癌症。提出了三个具体目标。AIM 1将使用体外方法来定义生物标志物 一组非小细胞肺癌患者对洛前列酮和罗格列酮的敏感性，并检查它们之间的相互作用 代理商和EGFR-TKI。目标2将使用化学致癌模型来检查组合 洛前列素联用罗格列酮和厄洛替尼的疗效。人非小细胞肺癌的异种移植将用于建立 Lloprost与Fzd9的相互作用。AIM 3将研究这一途径中的分子在 来自化学预防试验的样本，并将变化与不典型增生程度的变化和 对伊洛前列素或罗格列酮的反应。这一途径中的分子的表达将在人类身上进行检测 使用组织微阵列的肿瘤。这些研究将确定该通路在肺癌发生中的作用。 和进展，并帮助确定新的治疗目标。

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.