The translational goal of this project is to identify host characteristics that can be used to individually tailor colon cancer prevention therapy in order to reduce the development of clinically significant colorectal intraepithelial neoplasia (IEN) in humans with elevated risk for colon cancer. The hypothesis to be tested in this proposal is that individual responses to certain colon cancer preventive agents, including specific non-steroidal anti-inflammatory drugs (NSAIDS) and agents that target features of polyamine metabolism, are influenced by host factors, including genetic background, and diet.
Three specific aims are proposed to test this hypothesis. First, we will determine if genetic variability in the host gene encoding ornithine decarboxylase (ODC) can explain individual variability in colorectal mucosal polyamine contents. We will also determine if variability in the ODC and/or the flavin monooxygenase 3 (FM03) genes modulate the action and/or bioavailability of the chemopreventive agents sulindac and difluoromethylornithine (DFMO) when given in combination for the reduction of colon polyp recurrence. Second, we will determine if the association between the ODC G316A promoter variant alleles and adenoma recurrence in aspirin users involves other genes, which affect polyamine metabolism.
This aim will focus on the spermidine/spermine N1-acetyltransferase (SSAT), and determine if acetylated polyamines, which are substrates for polyamine export, may be a useful biomarker of NSAID action. Third, we will assess the independent and joint effects of aspirin use,dietary sources of polyamines, and gene modifiers of polyamine synthesis (ODC) on risk of colorectal adenoma recurrence. We will pool data from three adenoma recurrence studies, including the Polyp Prevention Trial (PPT), Wheat Bran Fiber (WBF) and Ursodeoxycholic Acid (UDCA) colon polyp prevention trials to assess these effects on overall adenoma recurrence and recurrence of advanced lesions. The long-term goal of this project is to determine the influence of host and adenoma factors as predictors of efficacy for the chemoprevention of colorectal adenomas, particularly advanced, clinically significant lesions, and to use this information to reduce the incidence of colorectal cancer in individuals with high risk of developing this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
3P50CA095060-10S2
Application #
8532079
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$599,996
Indirect Cost
$203,959
Name
University of Arizona
Department
Type
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Harpel, Kaitlin; Leung, Sarah; Rice, Photini Faith et al. (2016) Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. Phys Med Biol 61:N60-9
Hingorani, Dina V; Montano, Luis A; Randtke, Edward A et al. (2016) A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals. Contrast Media Mol Imaging 11:130-8
Tsikitis, Vassiliki L; Potter, Amiee; Mori, Motomi et al. (2016) MicroRNA Signatures of Colonic Polyps on Screening and Histology. Cancer Prev Res (Phila) 9:942-949
Fernández-Cuervo, Gabriela; Sinharay, Sanhita; Pagel, Mark D (2016) A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities. Chembiochem 17:383-7
Chang, Hae Ryung; Nam, Seungyoon; Kook, Myeong-Cherl et al. (2016) HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer. Gut 65:19-32
Daryaei, Iman; Randtke, Edward A; Pagel, Mark D (2016) A biomarker-responsive T2ex MRI contrast agent. Magn Reson Med :
Kurzius-Spencer, Margaret; Harris, Robin B; Hartz, Vern et al. (2016) Relation of dietary inorganic arsenic to serum matrix metalloproteinase-9 (MMP-9) at different threshold concentrations of tap water arsenic. J Expo Sci Environ Epidemiol 26:445-51
Rothlin, Carla V; Carrera-Silva, Eugenio A; Bosurgi, Lidia et al. (2015) TAM receptor signaling in immune homeostasis. Annu Rev Immunol 33:355-91
Kopetz, Scott; Tabernero, Josep; Rosenberg, Robert et al. (2015) Genomic classifier ColoPrint predicts recurrence in stage II colorectal cancer patients more accurately than clinical factors. Oncologist 20:127-33
Mercado-Pimentel, Melania E; Onyeagucha, Benjamin C; Li, Qing et al. (2015) The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells. FEBS Lett 589:2388-93

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