Epidemiologic and experimental studies have established that obesity is an important risk and/or prognostic factor for most cancer types, but the mechanisms underlying the obesity-cancer link have not been clearly elucidated. This knowledge gap is hampering efforts to develop mechanism-based strategies to more precisely intervene to prevent and control obesity-related cancers. Given the rising rates of obesity and cancer worldwide, and the challenges for many people to lose excess weight, I propose an integrated multilevel approach to address four critical questions that will lead to new, effective mechanism-based interventions to offset obesity-associated increases in cancer burden: i) Does moderate weight loss alone, or in combination with other mechanism-based interventions, reverse the procancer effects of obesity? ii) What are the mechanisms of (and solutions to) obesity-induced chemotherapeutic resistance? iii) What are the targets and strategies for offsetting the pro-metastatic effects of obesity? iv) What new targets for offsetting the effects o obesity can be identified by deconvoluting (and ultimately disrupting) the reciprocal crosstalk between adipocytes, macrophages and epithelial cells? The overarching goal is to capitalize on our expertise in energy balance and cancer research (including well-characterized preclinical models of breast, colon and pancreatic cancer and well-established collaborations spanning molecular/cellular biologic approaches to clinical trials and epidemiologic studies) to elucidate mechanistic targets, identify new biomarkers that can be used in parallel human and animal studies, and develop effective interventions to break obesity-cancer links and reduce the burden of cancer in obese people.

Public Health Relevance

Obesity is rising worldwide and we urgently need to better understand the biologic mechanisms underlying obesity-cancer links to develop more effective interventions to break those links. With a unique interdisciplinary approach combining well-characterized preclinical models in partnership with strong translational collaborations, I propose to identify new biomarkers and develop effective interventions to break obesity-cancer links and reduce the burden of obesity-associated cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197627-04
Application #
9531297
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Daschner, Phillip J
Project Start
2015-08-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Nutrition
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Rossi, Emily L; Khatib, Subreen A; Doerstling, Steven S et al. (2018) Resveratrol inhibits obesity-associated adipose tissue dysfunction and tumor growth in a mouse model of postmenopausal claudin-low breast cancer. Mol Carcinog 57:393-407
Bowers, Laura W; Rossi, Emily L; McDonell, Shannon B et al. (2018) Leptin Signaling Mediates Obesity-Associated CSC Enrichment and EMT in Preclinical TNBC Models. Mol Cancer Res 16:869-879
Smith, Laura A; O'Flanagan, Ciara H; Bowers, Laura W et al. (2018) Translating Mechanism-Based Strategies to Break the Obesity-Cancer Link: A Narrative Review. J Acad Nutr Diet 118:652-667
Himbert, Caroline; Ose, Jennifer; Nattenmüller, Johanna et al. (2018) Body fatness, adipose tissue compartments and biomarkers of inflammation and angiogenesis in colorectal cancer: the ColoCare Study. Cancer Epidemiol Biomarkers Prev :
Doerstling, Steven S; O'Flanagan, Ciara H; Hursting, Stephen D (2017) Obesity and Cancer Metabolism: A Perspective on Interacting Tumor-Intrinsic and Extrinsic Factors. Front Oncol 7:216
Romieu, Isabelle; Dossus, Laure; Barquera, Simón et al. (2017) Energy balance and obesity: what are the main drivers? Cancer Causes Control 28:247-258
Allott, E H; Macias, E; Sanders, S et al. (2017) Impact of carbohydrate restriction in the context of obesity on prostate tumor growth in the Hi-Myc transgenic mouse model. Prostate Cancer Prostatic Dis 20:165-171
O'Flanagan, Ciara H; Smith, Laura A; McDonell, Shannon B et al. (2017) When less may be more: calorie restriction and response to cancer therapy. BMC Med 15:106
Rossi, Emily L; Dunlap, Sarah M; Bowers, Laura W et al. (2017) Energy Balance Modulation Impacts Epigenetic Reprogramming, ER? and ER? Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice. Cancer Res 77:2500-2511
Ashkavand, Zahra; O'Flanagan, Ciara; Hennig, Mirko et al. (2017) Metabolic Reprogramming by Folate Restriction Leads to a Less Aggressive Cancer Phenotype. Mol Cancer Res 15:189-200

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