P1 - Omega-3 fatty acids and Colorectal Cancer Prevention

  • Ruffin, Mack (PI)
  • BRENNER, DEAN (PI)
  • SMITH, WILLIAM ALEXANDER (CoPI)
  • LAWRENCE, THEODORE (PI)
  • SIMEONE, DIANE (PI)
  • GIORDANO, THOMAS (PI)
  • TAYLOR, JEREMY MG (PI)
  • FEARON, ERIC (PI)
  • GRUBER, STEPHEN (PI)
  • BRENNER, DEAN (PI)
  • Taylor, Jeremy (PI)
  • SMITH, WILLIAM ALEXANDER (CoPI)
  • BRENNER, DEAN (PI)

Project: Research project

Project Details

Description

Project 1
There is a need to identify and develop more favorable therapeutic index-based cancer preventive
interventions. The overall goal of this project is to test the hypothesis that substituting iu3 fatty acids for 106
fatty acids in colorectal mucosal membranes will sufficiently modify the ratio of eicosapentaenoic acid (EPA)
to arachidonic acid (AA) available to prostaglandin-H synthases (PGHS)-1 and 2 to reduce local
prostaglandin (PG)E2 concentrations. Reduction of colonic mucosal PGE2 will reduce the carcinogenesis
stress and ultimately reduce the development of neoplasia in the colonic epithelium. We also hypothesize
that the dose of fish oil sufficient to reduce local PGE2 can be predicted by plasma EPAiAA ratio and thus be
individualized. The reduction of PGE2 concentrations sufficient to reduce proliferation and enhance
apoptosis of the colorectal mucosal crypt may be searched. Aim #1 will define tlie dose response to dietary
fish oil in mice and the relationshipo between the plasma and colonic mucosal EPA:AA ratio upon reduction
of PGE2 in colonic mucosa of PGHS-1 and -2 wild type mice will be fed diets formulated to match multiple
human fatty acid intakes. The plasma and colonic mucosal EPA:AA ratios and PGE2 concentrations in
colonic mucosa and urine will be assayed. Data in Aim 1 are necessary to define the design of a Phase I
clinical trial proposed in Aim 2. The clincal trial will determine if fish oil supplementation in humans on a
normal diet can produce a colorectal mucosal and plasma EPAiAA ratio defined in the mouse models that
will reduce colorectal mucosal PGE2, reduce colorectal crypt proliferation index and enhance apoptosis
indicies. A Bayesian driven biomarker adaptive phase I design individualizes dose on the basis of individual
biomarker response. The data obtained in this project will determine the feasibility, future design and
biomarker endpoints of Phase II clinical trials of u)3 fatty acids as potential preventives of colorectal
adenocarcinoma.
StatusFinished
Effective start/end date3/1/108/31/17