EICOSANOID PATHWAY TARGETS IN LUNG CANCER

环氧化酶-2（考克斯-2）表达上调，PGE合成酶增加，15-羟色胺（15-HT）表达下调。 前列腺素脱氢酶（15-PGDH）是在类花生酸途径中经常观察到的改变， NSCLC。单独或共同地，这些改变可能导致高PGE 2水平，这反过来促进 血管生成，影响细胞迁移和侵袭潜力的变化，改变细胞周期进程，减少 细胞凋亡和抑制免疫监视，其中每一个都有助于发展和增长， 非小细胞肺癌。因此，旨在降低PGE 2水平或改变PGE 2下游效应的努力， 应该证明对肺癌的治疗和预防都是有益的，但是考克斯的临床试验 迄今为止，肺癌的抑制剂在人体研究中显示出好坏参半的结果。 我们假设这些混合的结果是由于先前方法中的两个缺陷：1）缺乏有效的 允许选择可能受益的患者的生物标志物，和2）可用抑制剂的多效性作用 多种之前无法测量的花生四烯酸代谢物。在这个提案中，我们将使用一个候选人， 肿瘤内考克斯-2活性的生物标志物（尿PGE-M），我们在上一个资助期开发 为了前瞻性地识别一组我们认为对选择性考克斯具有“考克斯依赖性”的非小细胞肺癌肿瘤- 靶向治疗在这些和其他患者中，我们将系统地研究三个主要的家族， 代谢物PGE、PGI和LIE，以评估它们在NSCLC中的组合和单独重要性。 为了开始解决第二个问题，我们还将利用高选择性的抗肿瘤药物进行试点研究。 前列腺素受体，最初是PGE 2受体4（EP 4），我们已经证明可以显着抑制 转移，降低肿瘤侵袭和肿瘤运动性并增加细胞凋亡。 这些研究将通过特异性的免疫反应，在分子水平上确定人类肺癌的复杂途径。 癌症患者的生物化学测量，并开始定义特定的治疗目标的选择性 对个体肿瘤有益。

Upregulation of cyclooxygenase-2 (COX-2), increased PGE synthase and downregulation of 15- prostaglandin dehydrogenase (15-PGDH) are alterations in the eicosanoid pathway frequently observed in NSCLC. Individually or collectively these alterations may result in high PGE2 levels that in turn promote angiogenesis, effect changes in cellular migration and invasive potential, alter cell cycle progression, reduce apoptosis and inhibit immune surveillance each of which contributes to the development and growth of NSCLC. Accordingly, efforts designed to decrease PGE2 levels or to alter the downstream effects of PGE2 should prove beneficial both in the treatment and prevention of lung cancer, but clinical trials of COX inhibitors in lung cancer have shown mixed results in human studies to date. We hypothesize that these mixed results are due to two flaws in prior approaches: 1) lack of validated biomarkers allowing selection of patients likely to benefit, and 2) pleiotropic effects of the available inhibitors on multiple, previously unmeasured arachidonic acid metabolites. In this proposal, we will use a candidate biomarker of intratumoral COX-2 activity (urinary PGE-M) that we developed in the previous funding period to prospectively identify a cohort of NSCLC tumors we believe are "COX dependent" for selective COX- targeted therapy. In these and other patients, we will methodically study three of the main families of metabolites PGE, PGI, and LIE to assess their combined and separate importance in NSCLC. To begin to address the second problem, we will also pilot studies utilizing highly selective inhibitors of the prostaglandin receptors, initially the PGE2 receptor 4 (EP4), that we have shown can dramatically inhibit metastasis, decrease tumor invasion and tumor motility and to increase apoptosis. Together these studies will molecularly define a complex pathway in human lung cancer through specific biochemical measurements in cancer patients, and begin to define specific therapeutic targets of selective benefit in individual tumors.