Metastatic spread remains the most significant challenge to successful treatment of cancer. Localized disease can be removed surgically or treated with radiation therapy. However, the vast majority of morbidity and mortality for epithelial cancers including breast, melanoma, and ovarian cancer is due to invasion and metastasis. The growth factor-like lysophospholipids, lysophosphatidic acid (LPA) and sphingosine-1- phosphate (S1P), through their G protein-coupled receptors play a fundamental role in cancer metastasis. The present renewal application builds upon the experimentally validated computational models of several of these receptors and the novel synthetic compounds we designed and synthesized with predicted pharmacological properties. During the course of these studies, the lysophospholipase D enzyme linked to LPA production was identified by one of our team members as the previously known autocrine cancer motility factor, autotaxin (ATX). ATX expression and activity shows a positive correlation with the invasive properties of numerous cancers. Thus, in addition to the lysophospholipid receptor family, ATX has emerged as a critically important and novel therapeutic LPA target. The continuation application sets two objectives: 1. Obtain biochemical validation of the ligand-binding pocket of S1P1 and S1P2 receptors derived from computational models using photoaffinity labeling and apply the model to in silico screening for S1P2- specific non-lipid leads with anti-metastatic activity. 2. Evaluate cyclic-phosphatidic acid and other LPA analogs, generated during the previous funding period, for inhibition of autotaxin, invasion, and metastasis in vitro and in vivo. This project continues as a highly-integrated, joint investigation between four senior and one junior investigator. The proposed work built around the previous team that includes Drs. Tigyi (molecular pharmacology, receptor biochemistry), Parrill (computational modeling) and Miller (organic synthesis) and will involve new collaborations with Dr. Mills at MD Anderson Cancer Center, who will coordinate in vivo testing of anti-metastatic drug candidates, and Dr. Baker (junior faculty), who will assist with photoaffinity labels and mass spectrometry. ? ? ? ?
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