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 Pls 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.
Aim 1: To determine if levels of colonic 15-PGDH expression are a prognostic marker of individual's risk of developing colonic neoplasia.
Aim 2: 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.
Aim 3: 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.
Aim 4: 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.