Selenium Colorectal Cancer Chemoprevention Trials
Principal Investigator: PATRICIA ANN THOMPSON
Abstract: DESCRIPTION (provided by applicant): Colorectal adenomas (CRAs) are the benign precursors of most cases of colorectal cancer (CRC), a leading cause of cancer deaths;advanced CRAs are those most likely to progress to CRC. Although most CRAs can be removed at colonoscopy, 20-50% of individuals undergoing repeat colonoscopy 3-5 years later have metachronous, i.e. new, CRAs. Furthermore, a proportion of CRCs are not preventable through screening colonoscopy, necessitating alternative preventive strategies, such as chemoprevention. When given as a supplement, selenium (Se), a trace dietary mineral that is incorporated into specialized selenoproteins was previously shown to protect against CRC and prevalent CRAs as secondary endpoints in a non-melanoma skin cancer chemoprevention trial. Chemopreventive agents for CRC can be assessed in randomized controlled trials (RCTs) comparing metachronous CRA rates between intervention and placebo groups with results of effects on CRA recognized by the FDA as a CRC surrogate. No RCTs of Se supplements for CRC chemoprevention or for any other preneoplastic condition as the primary endpoint, have been reported. This application is for 3 years funding to complete The Selenium Trial (SeT);an RCT of Se, 200 5g daily as selenized yeast, for which randomization is completed. The primary study hypothesis is that treatment with Se yeast for 3 to 5 years will reduce the rate of metachronous CRAs without associated serious toxicities. Funding is requested to follow remaining SeT participants through study completion for all 1,800 participants in early 2014, and for data analysis and reporting. A major new study aim has been added to address the suggestion in recent published studies that excessive Se exposure may increase risk for type 2 diabetes (T2D). Although a mechanism for Se-related T2D in human is obscure, animal studies suggest that chronic activation of glutathione peroxidase 1 (GPX1), a potent anti-oxidant selenoprotein, may lead to the development of hyperinsulinemia, hyperglycemia, insulin resistance, and obesity. Therefore, the question of whether or not Se supplementation contributes to T2D has important public health implications. In the SeT cohort, we propose two approaches to studying the effects of Se on T2D, and insulin sensitivity and secretion: an epidemiological approach using the entire cohort;and assessment of the effect of Se supplementation on insulin secretion and sensitivity at the individual level using a modified oral glucose tolerance test in a sub- cohort of 300 subjects (150 on placebo and 150 on Se yeast). In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D.
Funding Period: 2011-08-01 - 2014-07-31
more information: NIH RePORT
- Risk Modification of Colorectal Adenoma by CYP7A1 Polymorphisms and the Role of Bile Acid Metabolism in CarcinogenesisBetsy C Wertheim
1515 North Campbell Avenue, Tucson, AZ 85724
Cancer Prev Res (Phila) 5:197-204. 2012..Furthermore, UDCA efficacy for CRA prevention may be modified by genetic variation in CYP7A1, limiting treatment benefit to a subgroup of the population. Cancer Prev Res; 5(2); 197-204. ©2011 AACR...
- Design and baseline characteristics of participants in a phase III randomized trial of celecoxib and selenium for colorectal adenoma preventionPatricia Thompson
University of Arizona Cancer Center, 1515 N Campbell Avenue, Tucson, AZ 85724, USA
Cancer Prev Res (Phila) 5:1381-93. 2012..Intervention effects on adenoma recurrence will be determined, and their modification by genetic background and baseline selenium level. The effect of selenium supplementation on risk for type II diabetes will also be reported...
- Biomathematical Evaluation of Colon Cancer Screening and PreventionGEORG E LUEBECK; Fiscal Year: 2013..The goal of this renewal is to further explore, via a biomathematical description of the natural history of CRC, how screening and interventions can be applied most effectively to reduce the mortality associated with CRC ..
- Colorectal Chemoprevention with Calcium and Vitamin DJOHN ANTHONY BARON; Fiscal Year: 2013....
- EARLY EVENTS IN ALZHEIMER PATHOGENESISSUE TILTON GRIFFIN; Fiscal Year: 2013..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
- Personalized Prevention of Colorectal CancerChang Yu; Fiscal Year: 2013....
- Comparative Mechanisms of Cancer ChemopreventionRoderick H Dashwood; Fiscal Year: 2013..This application is innovative and timely in bridging basic mechanisms, preclinical models, and human studies of epigenetics and diet. ..
- BIOLOGY OF NEUROENDOCRINE PEPTIDESMarc R Montminy; Fiscal Year: 2013..Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders ..
- Vitamin D and type 2 diabetes (D2d)Anastassios G Pittas; Fiscal Year: 2013....
- PREVENTION OF PROSTATE CARCINOGENESIS BY NEXT-GENERATION SELENIUMJunxuan Lu; Fiscal Year: 2013..The results may help to resurrect and advance the field of Se-prostate cancer chemoprevention research, redefining and changing mechanism paradigms of active Se form(s), cellular processes and molecular targets. ..
- Penn TREC Survivor CenterKathryn H Schmitz; Fiscal Year: 2013..abstract_text> ..
- DRUG ABUSE RESEARCH CENTERSolomon H Snyder; Fiscal Year: 2013....
- Diabetes Prevention in the Vitamin D and Omega-3 TrialYiqing Song; Fiscal Year: 2013....