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)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA150964-02
Application #
8555227
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
2011-09-14
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$419,743
Indirect Cost
$145,551
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Venkitachalam, Srividya; Guda, Kishore (2017) Altered glycosyltransferases in colorectal cancer. Expert Rev Gastroenterol Hepatol 11:5-7
Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361
Morris, Shelli M; Davison, Jerry; Carter, Kelly T et al. (2017) Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms. Int J Cancer 140:853-863
Cummings, Linda C; Thota, Prashanthi N; Willis, Joseph E et al. (2017) A nonrandomized trial of vitamin D supplementation for Barrett's esophagus. PLoS One 12:e0184928
Hu, Xiao; He, Yanhua; Wu, Liping et al. (2017) Novel all-hydrocarbon stapled p110?[E545K] peptides as blockers of the oncogenic p110?[E545K]-IRS1 interaction. Bioorg Med Chem Lett 27:5446-5449
Zhao, Yiqing; Scott, Anthony; Zhang, Peng et al. (2017) Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis. Oncotarget 8:48782-48793
Luebeck, E Georg; Curtius, Kit; Hazelton, William D et al. (2017) Identification of a key role of widespread epigenetic drift in Barrett's esophagus and esophageal adenocarcinoma. Clin Epigenetics 9:113
Petersen, Christine P; Meyer, Anne R; De Salvo, Carlo et al. (2017) A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach. Gut :
Kim, Jaeil; Do, Eun-Ju; Moinova, Helen et al. (2017) Molecular Imaging of Colorectal Tumors by Targeting Colon Cancer Secreted Protein-2 (CCSP-2). Neoplasia 19:805-816
Cohen, Andrea J; Saiakhova, Alina; Corradin, Olivia et al. (2017) Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome. Nat Commun 8:14400

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