Dr. Lynch and colleagues have used classical medicinal chemistry to generate a library of LPA structural analogs. In testing these novel chemical entities as cloned receptors and as substrates for the LPA ecto-phosphatases, the investigators identified compounds that are stable, receptor subtype-selective agonists and inhibitors of the phosphohydrolases. These tools allow, for the first time, delineation of the function of LPA signaling through endogenous receptors. The investigators now intend to use their existing compounds and others in development to learn whether LPA promotes prostate cancer progression. They will assign signaling events in LNCaP and PC-3 cells to specific LPA receptors thus both prioritizing LPA receptors for antagonist development and identifying compounds for testing on prostate cancer cell growth in vivo. Finally they will identify and quantify the species of LPA produced by prostate cancer cells to determine it suitability as a biomarker.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA088994-01
Application #
6226345
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Spalholz, Barbara A
Project Start
2001-01-05
Project End
2004-12-31
Budget Start
2001-01-05
Budget End
2001-12-31
Support Year
1
Fiscal Year
2001
Total Cost
$192,348
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Okusa, Mark D; Ye, Hong; Huang, Liping et al. (2003) Selective blockade of lysophosphatidic acid LPA3 receptors reduces murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 285:F565-74
Hasegawa, Yutaka; Erickson, James R; Goddard, Graham J et al. (2003) Identification of a phosphothionate analogue of lysophosphatidic acid (LPA) as a selective agonist of the LPA3 receptor. J Biol Chem 278:11962-9
Brinkmann, Volker; Davis, Michael D; Heise, Christopher E et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453-7
Im, D S; Clemens, J; Macdonald, T L et al. (2001) Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8): structure-activity relationship of sphingosine1-phosphate receptors. Biochemistry 40:14053-60