Cancer cell proliferation is driven by overexpression or mutational activation of normal cellular pathways that control cell growth and differentiation. Recent work suggests that autocrine actions of the receptor-directed lipid growth factor lysophosphatidic adid (LPA) play a central role in the etiology of ovarian cancer. Growth, invasiveness and resistance to chemotherapeutics of ovarian cancer cells are all dependent on LPA. Ovarian cancer cells synthesize LPA and release this mediator into ascites fluid which accumulates in the peritoneum and bathes abdominal tumors. Current therapies for late stage ovarian cancer that include surgery, radiation and chemotherapy have not improved cure rates for the disease. Targeting the synthesis and actions of LPA may therefore provide a novel treatment strategy for pharmacological intervention in ovarian cancer. Although the receptors and signaling pathways involved in responses to LPA are well understood surprisingly little is known about the enzymes and cellular processes involved in LPA synthesis, release and inactivation. We have identified phospholipases and lipid phosphatases that play critical roles in the synthesis and metabolism of LPA and related bioactive lipid mediators. The goal of the research described in this proposal is to define the enzymes and pathways involved in the synthesis and inactivation of LPA by ovarian cancer cells. Molecular genetic and pharmacological manipulation of these pathways will allow us to evaluate the potential for therapies that target LPA metabolism in treatment of ovarian cancer. Successful completion of the research will provide the framework and impetus to develop novel effective therapeutics for ovarian cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA096496-01
Application #
6496446
Study Section
Special Emphasis Panel (ZRG1-ET-1 (01))
Program Officer
Mohla, Suresh
Project Start
2002-02-01
Project End
2006-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$258,990
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Panchatcharam, Manikandan; Miriyala, Sumitra; Yang, Fanmuyi et al. (2008) Lysophosphatidic acid receptors 1 and 2 play roles in regulation of vascular injury responses but not blood pressure. Circ Res 103:662-70
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