EICOSANOID PATHWAY TARGETS IN LUNG CANCER

环氧合酶-2(COX-2)上调、前列腺素E合成酶(PGE)升高、15- 前列腺素脱氢酶(15-PGDH)是二十烷类途径中常见的一种改变。 非小细胞肺癌。单独或共同地，这些改变可能导致高PGE2水平，进而促进 血管生成，影响细胞迁移和侵袭潜能的变化，改变细胞周期进程，减少 细胞凋亡和抑制免疫监视，每一种都有助于肿瘤的发展和生长 非小细胞肺癌。因此，旨在降低PGE2水平或改变PGE2下游影响的努力 应该证明对肺癌的治疗和预防都是有益的，但COX的临床试验 到目前为止，肺癌抑制剂在人体研究中的结果喜忧参半。 我们假设，这些好坏参半的结果是由于先前方法中的两个缺陷：1)缺乏验证 允许选择可能受益的患者的生物标志物，以及2)可用的抑制剂的多效性效应 关于多种以前未测到的花生四烯酸代谢物。在这个提案中，我们将使用一位候选人 我们在前一资助期间开发的肿瘤内COX-2活性的生物标记物(尿PGE-M) 为了前瞻性地确定一组我们认为是选择性COX依赖的NSCLC肿瘤- 靶向治疗。在这些患者和其他患者中，我们将系统地研究三个主要的家族 代谢产物前列腺素E、前列环素和利尿以评估它们在非小细胞肺癌中的联合和单独的重要性。 为了开始解决第二个问题，我们还将进行试点研究，利用高度选择性的 前列腺素受体，最初是PGE2受体4(EP4)，我们已经证明可以显著抑制 转移，减少肿瘤侵袭，减少肿瘤运动，增加细胞凋亡。 这些研究将共同在分子上定义人类肺癌中的一条复杂的途径，通过特定的 对癌症患者进行生化检测，并开始确定选择性的特定治疗靶点 在个体肿瘤中受益。

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.