Project Leaders


Mack N. Barnes, M.D., Co-Leader

Objectives

The action of non-steroidal anti-inflammatory drugs (NSAIDS) and analgesic agents in reducing the risk of ovarian cancer has been suggested by several epidemiologic studies. However, detailed studies into the mechanisms of this potential class of chemopreventive agents in the context of human ovarian carcinoma are lacking. We hypothesize that NSAIDs provide a protective effect against ovarian cancer by mediation of serum and ovarian tissue inflammatory pathways and this protective effect may be influenced by genetic variations in inflammatory response pathways. As such, we will determine whether the relationship between NSAID/analgesic use and ovarian cancer risk is modified by genetic polymorphisms in specific inflammatory response pathways including genes involved in drug metabolism, drug effects (i.e., cycloxygenases), and those that mediate the actions of arachidonic acid metabolites. (Year 1 - 3). Epidemiologic data and DNA, available from approximately 1,600 subjects enrolled in the North Carolina Ovarian Cancer Study (NCOCS), a population based case-control study, will be used to assess the relationship between polymorphic variants of candidate genes affecting inflammatory response and the risk of developing ovarian cancer. The effect of candidate genes on the relationship between analgesic use and ovarian cancer risk will be evaluated. As an extension of findings sought on the population level, we will also pursue a clinical trial using aspirin to obtain data regarding the effect of NSAIDs on inflammatory mediators thought to be active at the serum and ovarian tissue level in high risk subjects. As such, in years 1-4, a clinical trial using enteric coated aspirin (325mg QD) will then be initiated in women who will be undergoing oophorectomy for risk reduction (“high risk cohort”) with the action of aspirin on serum proteins and ovarian tissue compartments analyzed with a focus on identification of alteration in inflammatory mediators. Within the “high risk” cohort, where the entire ovary must be preserved to pathologically rule out occult cancer, surface epithelial cell protein alterations will be studied using a minimally invasive method of performing proteomics on ovarian surface epithelium. The ultimate goal of this project is to determine the effect of these compounds on human serum and ovarian tissues and discover surrogate gene expression markers for these effects that could be utilized in larger scale chemoprevention trials for ovarian cancer. This project takes advantage of a collaboration with experienced investigators at Duke University and makes extensive use of immunohistochemistry, proteomic and pathology expertise from Core C, statistics from Core B, and administrative support from Core A.