This is a resubmission of a competitive renewal application in response to PAR-09-025 entitled """"""""National Cancer Institute Program Project (PO1) Applications"""""""". The funding requested will continuously support this highly productive Program Project Grant 5P01-CA077839 and extend the original goals of this successful P01. This proposal will focus on """"""""The Role of Bioactive Lipids in Inflammation and Cancer"""""""". Chemoprevention represents one potential approach to reduce the cancer burden. For example, use of NSAIDs including aspirin and selective GOX-2 inhibitors (COXIBs) has been suggested to reduce the risk of several different malignancies. Although the link between GOX-2 and carcinogenesis is well established, prolonged use of COXIBs is associated with an increased risk of cardiovascular complications. Given the recognized importance of prostaglandin E2 (PGE2) in carcinogenesis, a cutting-edge goal of chemoprevention research is to find alternative COX-2-independent approaches to suppress PGE2 production or to block the downstream procarcinogenic effects of this bioactive lipid. Alternatively, a potential strategy for optimizing the therapeutic index of COXIBs is to develop effective combination chemoprevention regimens that will allow the dose of COXIB to be reduced. These different strategies will be pursued in this PPG. In addition, bioactive lipids play a key role in inflammation and carcinogenesis. Bioactive lipids such as eicosanoids, endocannabinoids, sphingolipids, and ceramides can initiate complex signaling networks that affect carcinogenesis. In the current proposal, four projects are planned. The individual projects focus on: 1) The roles of PGE2 and endocannabinoids coordinately in controlling colorectal cancer cell fate;2) Targeting the obesity-COX-PGE2-aromatase axis to reduce breast cancer risk;3) Defining the role of sphingolipid mediators in intestinal tumorigenesis and 4) Investigating the role of Pten-Cox2-mTOR signaling in endometrial cancer. Consistent with past efforts, important collaborations will occur between project leaders. These interactions are crucial for success. The Administrative Core A will provide oversight and facilitate interactions between each of the projects. The Analytical Core B will provide analysis of bioactive lipids including eicosanoids, endocannabinoids and sphingolipids. Successful completion of the proposed studies will improve the overall understanding of the link between bioactive lipids and carcinogenesis. Information gained from these studies will be important for achieving the long-term goal of reducing the cancer burden and revealing more effective ways to prevent cancer.
The overall objective of this program is to better understand the role of bioactive lipids in the biology of inflammation and cancer as the basis for rational risk reduction interventions. Armed with these insights, new preventive strategies will be explored. By achieving our overall goals, new knowledge about bioactive lipid signaling networks is expected to have significant preclinical and eventually clinical-translational impact.
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