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. A fundamental question that remains unanswered is whether the metabolic and/or molecular perturbations underlying obesity-cancer links can be reversed with modest weight loss. Our preliminary data from human-mouse co-trials suggest that moderate weight loss alone may not be sufficient to reverse the procancer effects of chronic obesity, at least in part due to epigenetic reprogramming of inflammatory and other pathways that do not reverse with normalization of weight alone. Two other understudied aspects of the obesity-cancer link are the mechanisms of and solutions to the diminished response to many chemotherapeutic drugs in obese patients, and the impact of obesity on processes related to cancer metastases, the ultimate cause of death in most fatal cancer cases. Given the rising rates of obesity and cancer worldwide, and the challenges for many people to lose excess weight, we propose an integrated multilevel approach to address these critical questions and efficiently identify and validate key molecular targets that will lead to new, effective mechanism-based interventions to offset obesity-associated increases in cancer burden is highly innovative and transformative. The objective of this multi-level approach is to integrate our work on 3 different cancers (breast, pancreatic and colon) and bridge: a) strong preclinical research--we have developed and used multiple genetically-engineered mouse models (GEMMs) for each cancer site that are well-suited to the types of dietary studies we are proposing, and also have derived cell lines for in vitro and orthotopic transplant studies to complement our GEMM studies. We are also working with Ned Sharpless, Chuck Perou and others to develop new models for studying obesity and cancer, including capitalizing on the genetic diversity and range of body size phenotypes of novel mouse lines within the Collaborative Cross program at UNC; b) clinical trials (such as the human-mouse co-trial approach we are taking with Dr. Carol Fabian at Kansas Cancer Center) or epidemiologic studies to validate and extend our preclinical findings and accelerate the pace of translating this work to preventing human cancers; c) combining the strengths in my lab in nutrition, organismal metabolism, and cell and molecular biology with the strengths in genomics (with Chuck Perou and colleagues), metabolomics (with Liza Makowski and colleagues), epigenetics (with Scott Bultman and colleagues) at UNC and in secretomics through our collaboration with Stephan Herzig in Heidelberg, to identify new targets and strategies for breaking obesity-cancer links; d) outstanding access to human samples at UNC, such as the Carolina Breast Cancer Study and Normal Breast Study (led by Andy Olshan and Melissa Troester), Aurora-US (a Breast Cancer Research Foundation-funded initiative based at UNC under the direction of Chuck Perou and Lisa Carey) that utilizes the extensive clinical trial infrastructure of the Translational Breast Cancer Research Consortium for clinical trial development and molecular and pathological evaluation of metastatic breast cancer samples), several large colon cancer prevention trials and registries led by John Baron, and a large repository of pancreatic cancer patients managed by Joel Tepper (PI of UNC’s emerging Pancreatic Cancer SPORE). The ultimate goal of this proposal is to build on our previous contributions to the field by developing transdisciplinary teams to translate key findings into new approaches to decreased cancer burden in obese women and men.
|Effective start/end date||8/1/15 → 7/31/22|
- NIH National Cancer Institute (NCI)
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