Inhibition of cyclooxygenase (COX) prevents lung cancer in animal models. Prostaglandin I-2 (PGI-2, prostacyclin) is a COX metabolite with anti-inflammatory, anti-proliferative, and potent anti-metastatic properties. Until recently, the instability of PGI-2 formulations have limited their evaluation in cancer models. In our previous studies, transgenic mice with selective pulmonary PGI-2 synthase (PGIS) overexpression were exposed to two distinct carcinogenesis protocols. The transgenic mice exhibited significantly reduced lung tumor multiplicity and incidence. While COX inhibition is attractive as a chemopreventive strategy, our findings suggest that manipulation of the araehidonic acid pathway downstream from COX may prove even more promising. These data have resulted in a clinical trial in which patients at high risk for lung cancer will be treated with the PGI-2 analog Iloprost. The goal of this project is to examine the role of PGI-2 in the development of human lung tumors, and to define the mechanism of the protective effect of PGI-2.
Four specific aims are proposed.
In Specific Aim 1, the expression of PGIS and other enzymes in this pathway will be quantitated and localized using tissue arrays provided by the SPORE. Expression will be correlated with type of cancer and clinical outcomes. Biopsies will also be obtained from patients enrolled in the Iloprost clinical trial and analyzed for global patterns of gene expression using Affymetrix GeneChips.
Specific Aim 2 will delineate whether the protective effects of PGI-2 are mediated through a cell surface receptor or other target. Tumor formation will be examined in mice lacking the cell surface receptor for PGI-2 (PGIR) using a well characterized carcinogenesis protocol. In addition, double transgenic mice have been obtained by crossing PGIS Tg+ mice into the PGIR(-/-) mice. The susceptibility of these mice to develop tumors will be compared with PGIS Tg+ mice previously studied Specific aim 3 is designed to determine if combination therapy using Iloprost and COX inhibitors will lead to greater inhibition of carcinogenesis than either agent alone in murine models.
Specific aim 4 will examine the mechanisms whereby PGIS is protective against developing lung cancer. Multiple NSCLC lines have been developed which stably overexpress PGIS. The effect of overexpression on growth and apoptosis will be determined. The ability of these cells to form tumors in athymic mice will also be examined. Mouse tumor cells will be inoculated into PGIS-Tg+ mice and wild-type controls to examine the role of PGIS in the host. These studies will provide insight into the mechanisms of chemoprotection by PGI-2 and in conjunction with the clinical Iloprost chemoprevention trial, may define new approaches to lung cancer prevention and treatment.
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