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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092160-07
Application #
7286662
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
2001-08-01
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$285,892
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Dancs, Péter Tibor; Ruisanchez, Éva; Balogh, Andrea et al. (2017) LPA1 receptor-mediated thromboxane A2 release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction. FASEB J 31:1547-1555
Lin, Kuan-Hung; Ho, Ya-Hsuan; Chiang, Jui-Chung et al. (2016) Pharmacological activation of lysophosphatidic acid receptors regulates erythropoiesis. Sci Rep 6:27050
Ragle, Lauren E; Palanisamy, Dilip J; Joe, Margaux J et al. (2016) Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition. Bioorg Med Chem 24:4660-4674
Knowlden, Sara A; Hillman, Sara E; Chapman, Timothy J et al. (2016) Novel Inhibitory Effect of a Lysophosphatidic Acid 2 Agonist on Allergen-Driven Airway Inflammation. Am J Respir Cell Mol Biol 54:402-9
Deng, Wenlin; Kimura, Yasuhiro; Gududuru, Veeresh et al. (2015) Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. Radiat Res 183:465-75
Lee, Sue-Chin; Fujiwara, Yuko; Liu, Jianxiong et al. (2015) Autotaxin and LPA1 and LPA5 receptors exert disparate functions in tumor cells versus the host tissue microenvironment in melanoma invasion and metastasis. Mol Cancer Res 13:174-85
Zhao, Guannan; Guo, Yuqi; Chen, Zixuan et al. (2015) miR-203 Functions as a Tumor Suppressor by Inhibiting Epithelial to Mesenchymal Transition in Ovarian Cancer. J Cancer Sci Ther 7:34-43
Balogh, Andrea; Shimizu, Yoshibumi; Lee, Sue Chin et al. (2015) The autotaxin-LPA2 GPCR axis is modulated by ?-irradiation and facilitates DNA damage repair. Cell Signal 27:1751-62
Parham, Kate A; Zebol, Julia R; Tooley, Katie L et al. (2015) Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-? that regulates neoangiogenesis. FASEB J 29:3638-53
Lee, Sue-Chin; Fujiwara, Yuko; Tigyi, Gabor J (2015) Uncovering unique roles of LPA receptors in the tumor microenvironment. Receptors Clin Investig 2:

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