The Principal Investigators of this proposal are discovers of a novel and potent colon cancer suppressor pathway mediated by the colon cancer suppressor gene 15-Prostaglandin Dehydrogenase (15-PGDH). 15- PGDH controls the rate limiting step in the degradation of bioactive prostaglandins. As such, it is metabolically poised to antagonize the prostaglandin generating activity of the COX-2 oncogene, which is well characterized as being markedly up-regulated in most colon cancers and precancerous colon adenomas. The P.l.s have shown: i) that 15-PGDH is highly expressed by normal colonocytes, but that expression is dramatically lost in 90% of colon cancers;ii) that restoring 15-PGDH expression by gene transfection blocks colon cancer xenograft growth;iii) that gene knockout of murine 15-PGDH promotes development of murine colon tumors;iv) and that low levels of colonic 15-PGDH confers resistance to the colon tumor preventive effects of Celecoxib in murine models and in a pilot study of human subjects. Key translational research objectives of this project are now: i) to determine if levels of colonic 15-PGDH expression are a prognostic marker of individual's risk of developing colonic neoplasia;il) to determine if 15- PGDH expression Is a prognostic marker of colon cancer outcome;specifically, to determine whether the 10% of colon cancers that continue to express 15-PGDH represent either a less aggressive or a more aggressive form of the disease;iii) to determine If low levels of colonic 15-PGDH defines a cohort of individuals who are resistant to the chemopreventive effects of Celecoxib;specifically to extend a pilot analysis demonstrating this effect to a comprehensive study comparing colonic 15-PGDH levels versus outcome in over 450 individuals at high risk for colon neoplasia who were studied in the Adenoma Prevention with Celecoxib human trial;and iv) to identify and characterize small molecules that can reinduce 15-PGDH in colon cancer cells and can increase 15-PGDH expression in normal colon;this to be done by performing a high throughput screen of a chemical compound library of over 200,000 small molecules in a sensitive cell based 15-PGDH reporter assay.
Colon cancer is the second leading cause of cancer deaths among American adults. We have shown 15- PGDH mediates a novel anti-colon cancer pathway. This research will determine whether measurements of 15-PGDH can help identify individuals at high risk for colon cancer, can help in selecting individuals for the most effective colon cancer prevention treatments, and can be used to design new anti-colon cancer drugs.
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