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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50CA150964-04
Application #
8711342
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kendall, Bradley J; Rubenstein, Joel H; Cook, Michael B et al. (2016) Inverse Association Between Gluteofemoral Obesity and Risk of Barrett's Esophagus in a Pooled Analysis. Clin Gastroenterol Hepatol 14:1412-1419.e3
Thota, Prashanthi N; Zackria, Shamiq; Sanaka, Madhusudhan R et al. (2016) Racial Disparity in the Sex Distribution, the Prevalence, and the Incidence of Dysplasia in Barrett's Esophagus. J Clin Gastroenterol :
Parameswaran, Reshmi; Ramakrishnan, Parameswaran; Moreton, Stephen A et al. (2016) Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat Commun 7:11154
Peyser, Noah D; Wang, Lin; Zeng, Yan et al. (2016) STAT3 as a Chemoprevention Target in Carcinogen-Induced Head and Neck Squamous Cell Carcinoma. Cancer Prev Res (Phila) 9:657-63
Cui, Min; Awadallah, Amad; Liu, Wendy et al. (2016) Loss of Hes1 Differentiates Sessile Serrated Adenoma/Polyp From Hyperplastic Polyp. Am J Surg Pathol 40:113-9
Venkitachalam, Srividya; Revoredo, Leslie; Varadan, Vinay et al. (2016) Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer. Sci Rep 6:23642
Fecteau, Ryan E; Kong, Jianping; Kresak, Adam et al. (2016) Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia. JAMA Oncol 2:1333-1339
Sun, Xiangqing; Elston, Robert C; Barnholtz-Sloan, Jill S et al. (2016) Predicting Barrett's Esophagus in Families: An Esophagus Translational Research Network (BETRNet) Model Fitting Clinical Data to a Familial Paradigm. Cancer Epidemiol Biomarkers Prev 25:727-35
Russo, Suzanne; Ammori, John; Eads, Jennifer et al. (2016) The role of neoadjuvant therapy in pancreatic cancer: a review. Future Oncol 12:669-85
Eads, Jennifer R; Beumer, Jan H; Negrea, Lavinia et al. (2016) A pharmacokinetic analysis of cisplatin and 5-fluorouracil in a patient with esophageal cancer on peritoneal dialysis. Cancer Chemother Pharmacol 77:333-8

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