Lysophosphatidic acid (LPA), the simplest of all phospholipids, exhibits pleiomorphic functions in multiple cell lineages. The effects of LPA appear to be mediated by binding of LPA to specific members of the endothelial differentiation gene (Edg, Edg1, 2, 4, and 7) are activated by LPA) family of G protein-coupled receptors (GPCR) and potentially to PSP24. The specific biochemical events initiated by the different Edg receptors, as well as the biological outcomes of activation of the individual receptors, are only beginning to be determined. The importance of LPA in ovarian cancer is suggested by the fact that LPA levels are elevated in the plasma and ascites of ovarian cancer patients, but not in most other tumor types. Indeed, LPA levels are elevated in more than 90% of ovarian cancer patients suggesting that LPA may be a novel diagnostic or prognostic marker. Furthermore, ovarian cancer cells demonstrate markedly different responses to LPA than does normal ovarian surface epithelium. Different LPA receptors of the Edg family are expressed by normal and malignant ovarian epithelial cells. Thus, increased levels of LPA, altered receptor expression and altered responses to LPA all may contributed to the initiation, progression of outcome of ovarian cancer. We have developed a series a series of LPA analogs, which act as agonists and antagonists for specific LPA receptors on ovarian cancer cells. These analogs will not only be used to probe the function of the LPA receptors in ovarian cancer but also as lead compounds for therapeutic development. Indeed, over 60% of all drugs currently in use target the GPCR family, with many of these drugs being ligand analogs. Understanding the mechanisms regulating LPA production and function of the LPA receptors in ovarian cancer but also as lead compounds for therapeutic development. Indeed, over 60% of all drugs currently in use target the GPCR family, with many of these drugs being ligand analogs. Understanding the mechanisms regulating LPA production and function could lead to improved methods for early detection and to new targets for therapy. To accomplish this, we will: 1. Identify the receptors mediating specific LPA responses in ovarian cancer cells 2. Determine whether LPA is an appropriate target for therapy in ovarian cancer 3. Determine the source and mechanisms for elevated LPA levels in ovarian cancer patients 4. Determine whether measuring LPA levels can be used in early diagnosis, evaluation of intraperitoneal masses of management of ovarian cancer patients.
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