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.
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