Grant Details
Grant Number: |
2R01CA119171-18 Interpret this number |
Primary Investigator: |
Neuhouser, Marian |
Organization: |
Fred Hutchinson Cancer Center |
Project Title: |
Nutrition and Physical Activity Assessment Study (NPAAS) |
Fiscal Year: |
2024 |
Abstract
PROJECT SUMMARY
This competing renewal of CA119171-17 “Nutrition and Physical Activity Assessment Study” (NPAAS)
continues to focus on dietary biomarker discovery and application of these biomarkers to investigations of diet
and risk of cancer and other chronic diseases in the Women’s Health Initiative (WHI). In our recent funding
cycles, we developed novel metabolomics and stable isotope ratio biomarkers of diet in the NPAAS Feeding
Study and the NPAAS Observational Study and used these biomarkers to model diet-chronic disease
associations in older women. We now turn to the WHI Dietary Modification (WHI-DM) Trial where gaps remain
in understanding the biology of the intervention effects (both a priori hypothesized and those observed with
further interrogations of the data) and in the interpretation of intervention effects on clinical outcomes. Our
goals for this renewal are to use targeted metabolomics to delineate effect biomarkers and biological
mechanisms underlying WHI-DM intervention effects and to elucidate the role of the dietary fat reduction
intervention component in observed findings. The WHI-DM, a 2-arm randomized controlled trial in 48,835
women, was designed to test whether a low-fat (20% of total kcal) dietary pattern including 5 daily servings of
fruits and vegetables and 6 daily servings of grains would reduce risk of invasive breast and colorectal cancers
in postmenopausal women. While neither invasive breast nor colorectal cancers were significantly reduced by
the ~8.5 y intervention (P=0.09 and P=0.45, respectively), women in the intervention arm experienced
numerous clinically meaningful effects on important measures of metabolic health and long-term health and
mortality outcomes. Many differences in clinical factors (e.g., metabolic syndrome, body weight) between
intervention and comparison groups were detected early in the trial and are risk factors for several cancers.
Metabolomic profiling may uncover mechanistic underpinnings of these findings since these small molecules
are responsive to diet change and reflect biological phenotype. Our specific aims are 1) Evaluate the effect of
the WHI-DM intervention on the targeted serum metabolome and lipidome and biochemical pathways; 2)
Investigate how the metabolites mediate intervention effects on body measurements and intermediate
biomarkers of metabolic health; and 3) Elucidate the contribution of the trial’s fat reduction to intervention
effects. In collaboration with the Northwest Metabolomics Research Center, we will use established targeted
metabolomics platforms to interrogate archived serum collected at baseline and year 1 among 1000 WHI-DM
women (500 intervention arm/500 comparison arm) and in a subset (n=465) of this 1000 at end of intervention.
Results will elucidate biochemical pathways related to downstream risk for breast, colorectal, endometrial, and
total cancer, as well as obesity and other chronic diseases. Results are expected to reveal metabolic pathways
that explain the clinically meaningful effects from a large low-fat, high fruit and vegetable dietary pattern
intervention and to provide insight into the dietary fat reduction in yielding these intervention effects.
Publications