? There is strong biologic plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans, and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways (ARC, beta-catenin, E-cadherin, MLH1), 3) cell cycle events in colorectal epithelial crypt cells (long-term proliferation: telomerase; apoptosis inhibition and promotion: bcl-2, bax), and 4) autocrine/paracrine growth promotion and inhibition factors (TGFalpha, TGFbeta1,) that has not yet been tested in a chemoprevention trial. To address these needs, we will add measuring this biomarker panel to an ongoing multi- center, randomized, double-blind, placebo-controlled, 2x2 factorial clinical trial (n = 1,964) testing the efficacy of calcium 1,200 mg/day and/or vitamin D31,000 ILJ/day vs placebo in reducing recurrent sporadic colorectal adenomas over 3-5 years, in order to determine whether calcium and/or vitamin D can favorably modulate the panel of biomarkers and whether this modulation predicts adenoma recurrence. For the biomarker measurements, biopsies of normal- appearing rectal mucosa will be obtained from 1,328 (68%) of participants at 3- or 5-year follow-up colonoscopy. In addition, on a subset (n = 200) of these participants (50/treatment group), biopsies of normal-appearing rectal mucosa will be taken 'non-prep' at randomization, one year following randomization, and two weeks prior to 3 - 5 year follow-up colonoscopy; biopsies of normal appearing mucosa will also be taken from three colon sites (rectum, mid- sigmoid colon, and proximal ascending colon) during follow-up colonoscopies. We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of investigating the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, in modulating a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia, and determining whether this modulation predicts reduced recurrence of colorectal neoplasms. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA114456-01A1
Application #
7038411
Study Section
Special Emphasis Panel (ZRG1-CDP (01))
Program Officer
Malone, Winfred F
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$376,992
Indirect Cost
Name
Emory University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Liu, Siyu; Barry, Elizabeth L; Baron, John A et al. (2017) Effects of supplemental calcium and vitamin D on the APC/?-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients. Mol Carcinog 56:412-424
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Long, Qi; Zhang, Xiaoxi; Bostick, Roberd M (2011) Semiparametric estimation for joint modeling of colorectal cancer risk and functional biomarkers measured with errors. Biom J 53:393-410
Long, Qi; Flanders, W Dana; Fedirko, Veronika et al. (2010) Robust statistical methods for analysis of biomarkers measured with batch/experiment-specific errors. Stat Med 29:361-70