TREC Grantees & Projects

Scientists at the National Cancer Institute (NCI), four research centers, and a coordination center collaborate on the Transdisciplinary Research on Energetics and Cancer (TREC) initiative to study the complex relationships between obesity, energy balance, nutrition, physical activity, and cancer risk.

Research Centers

Harvard University
Principal Investigator: Frank Hu, M.D., Ph.D., M.P.H.
The Harvard TREC Research Center focuses on biological mechanisms linking obesity and cancer throughout the lifespan and at multiple levels, and translating this knowledge into actionable behavioral interventions targeting children, minorities, and cancer survivors.


In response to the National Cancer Institute re-issue of the Transdisciplinary Research on Energetics and Cancer (TREC) initiative (RFA-CA-10-006), we propose to establish a TREC Center that draws on the multidisciplinary expertise of the faculty of Harvard University at the Harvard School of Public Health (HSPH), Harvard Medical School and the Harvard-affiliated Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber/Harvard Cancer Center (DF/HCC; an NCI-designated Comprehensive Cancer Center), Harvard Pilgrim Health Care Institute, and the Harvard Center for Population and Development Studies. We have developed four complementary and interrelated research projects which are supported by four cores and additional existing resources of the participating institutions. Together, they form a cohesive, transdisciplinary center focused on the generation of new knowledge and its translation, training, and career development. In Project 1, we will examine sleep duration, energy balance, and insulin resistance among children in Project Viva; in Project 2, we will examine the relation of energetic factors (including dietary insulin demand, objectively measured energy expenditure and physical activity), sleep duration, and the built environment with novel cancer biomarkers (insulin-IGF axis, adipokines, and sex hormones) in the Nurses' Health Study; in Project 3, we will examine the relation of energetic factors (dietary insulin demand, adiposity, and physical activity) and biomarkers of the Insulin/IGF pathway with prostate cancer survivorship in the Physicians' Health Study; and in Project 4, we will conduct a randomized trial to evaluate whether a theory-based exercise intervention, alone or in combination with a pharmacological intervention, decreases circulating levels of insulin and other biomarkers previously linked to poor prognosis among colorectal cancer survivors. These projects will be supported by four cores: Administrative, Education/Training, Bioinformatics, and Developmental. Through these highly integrated projects and supporting Cores, we aim to train postdoctoral fellows and junior faculty in a transdisciplinary research environment to pursue careers in energetics and cancer and to foster innovative transdisciplinary research projects that build on the Center's and the overall TREC program's vision and resources. We have obtained strong institutional commitment, as outlined in the letters from Dr. Julio Frank, Dean of the Faculty, Harvard School of Public Health, and Dr. Edward Benz, Director of the DF/HCC and President of the Dana-Farber Cancer Institute. By leveraging multiple areas of expertise and different resources within and across TREC centers, we can help further build a unique national resource of energetics and cancer knowledge.

Sleep Duration, Childhood Energy Balance, and Insulin Resistance in Children
Childhood obesity is highly prevalent, spares no age group, and disproportionately affects racial/ethnic minority populations. Obesity in childhood is associated with adverse cardio-metabolic outcomes including hyperinsulinemia and insulin resistance which may, in turn, increase risks for many cancers. The lifecourse approach to chronic disease prevention posits that the right influences during infancy and early childhood could entrain healthful trajectories of weight and energy balance for life.

Mounting epidemiologic evidence indicates that short duration of sleep is a risk factor for obesity, insulin resistance, coronary heart disease, and all-cause mortality in adults independent of other risk factors. In addition, short-term experimental studies show that sleep restriction in adults is associated with physiologic mechanisms that may increase risk of adiposity and cardio-metabolic disorders. Yet major questions remain regarding the extent to which short sleep duration predicts adiposity and cardio-metabolic disorders in young children, and the potential mechanisms underlying these associations. Furthermore, few studies have examined the social-environmental context of early childhood sleep patterns that could inform behavioral interventions to improve sleep in high-risk groups.

The goals of this study are two-fold. The first goal is to examine associations of sleep duration - a novel risk factor for obesity and metabolic dysfunction identified in the first wave of TREC projects - in infancy and childhood with adiposity and energy balance, and with the emergence of insulin resistance and other cancer-related biomarkers in early adolescence. We will carry out this part of the project within the well-characterized pre-birth cohort study, Project Viva. This US-based study has prospectively collected and validated sleep and diet information, anthropometry, and research-quality biomarker data in children from early infancy through age 11 years. The second goal is to examine the social-cultural, behavioral, and environmental context of early childhood sleep patterns that could inform behavioral interventions to improve sleep duration and quality.

To achieve our aims, we have assembled a transdisciplinary research team of obesity and sleep medicine epidemiologists, behavioral scientists, clinical psychologists, pediatric clinical investigators, statisticians, and geneticists. The results of this study could strengthen the understanding of sleep, energy balance, and carcinogenesis from micro- (genetics) to macro- (environment) levels among children - a segment of the population at high risk for obesity and its sequelae. Furthermore, our study will supply key data needed for the design of future intervention studies, such as quantifying threshold levels of sleep that confer increased risk of obesity and metabolic dysfunction, identifying key proximate behaviors that mediate these associations, and identifying socio-cultural/environmental factors as potential targets for sleep improvement interventions.

Environmental and Lifestyle Factors, Obesity and Cancer-related Biomarkers
Disturbances in the insulin- insulin-like growth factor (IGF) axis, levels of sex hormones, and adipocytokines have been implicated in pathways connecting obesity with the development of several major cancers. However, few studies have sought to determine the origins of variation in these cancer-related biomarkers, which may be due to complex interrelationships between energetic factors such as diet, physical activity, and sleep patterns. Energetic factors may also be impacted by macro-level factors such as neighborhood social economical status (SES) and built environment. Finally, these relationships may be moderated by genetic variants, but little is known regarding this. In the first Aim, we will examine associations between energetic factors and cancer-related biomarkers in about 750 women (including 25% African American women) in the Nurses' Health Study. Energetic factors will include: (1) energy expenditure measured by doubly labeled water (DLW); (2) dietary insulin demand measured by insulin index and insulin load; (3) physical activity assessed by repeated accelerometer measurements; and (4) sleep duration assessed by two 1-week sleep logs. Cancer-related biomarkers will include (1) insulin-IGF axis components (fasting insulin, proinsulin, C-peptide, IGF-1, and IGFBP-3); (2) adipokines (total and free leptin [the ratio of leptin to soluble leptin receptor - sOB-R] and adiponectin); and (3) sex hormone-binding globulin (SHBG) and estradiol. In the second Aim, we will examine the relationships between neighborhood SES and built environment (assessed by the county sprawl index) and cancer-related biomarkers, and delineate the pathways linking these macro-level variables, energetic factors, biomarkers, and obesity. In the third Aim, we will examine whether genetic factors related to insulin resistance or insulin secretion modify the associations between behavioral (dietary insulin demand, physical activity, and sleep duration) and macro-level (neighborhood SES and built environment) factors and risk of obesity and long-term weight gain among 8,000 men and women in the Nurses' Health Study and Health Professionals Follow-up Study with available genome-wide association studies (GWAS) data. The findings from this study will not only provide insights into social, behavioral, and biological pathways underlying the relationship between energy balance and cancer risk, but also facilitate development of multi-tiered risk reduction strategies spanning diet and lifestyle modification to urban planning and community outreach for obesity and cancer prevention. Because the proposed study is based on well-established ongoing cohorts, and detailed measures of energetic factors (DLW, diet, physical activity, and sleep) and blood collection have been funded through a 2-year stimulus grant (2009-2011) by NCI, it is extremely cost-effective and timely.
PI: Frank Hu, M.D., Ph.D.

Energetic Factors, Fatal Prostate Cancer and Survivorship
In the United States, prostate cancer (PCa) is the most commonly diagnosed and second-most lethal cancer in men. Widespread prostate-specific antigen (PSA) screening has led to an increase in PCa incidence and a shift in stage at diagnosis with 90% of tumors now being localized at diagnosis. However, the determination of clinical features (PSA, clinical stage, and Gleason grade) alone has limited ability to identify patients at substantially elevated risk of PCa-specific mortality. A better understanding of the biology of lethal PCa and identification of novel markers of aggressive disease are urgently needed to develop effective therapeutic and preventive strategies. Excess body weight is consistently linked to PSA recurrence in numerous clinical studies, but its role in PCa-specific and total mortality in PCa patients remains unclear. Our intriguing preliminary findings on the relations of body mass index (BMI), C-peptide (a marker of insulin production), and adiponectin with fatal PCa support important roles of insulin/insulin-like growth factor (IGF) axis in pathways connecting energy balance and obesity to cancer progression and survival. In this application, we plan to extend this exciting work to comprehensively evaluate energetic factors and PCa-specific and all-cause mortality in men diagnosed with PCa, accounting for competing causes of death. These factors include adiposity (BMI, waist and hip circumference, and weight gain) and Type 2 diabetes (Aim 1), biomarkers (C-peptide, insulin, proinsulin, proinsulin/insulin ratio, IGF-1, IGF binding protein-3, and adiponectin; Aim 2), and genetic variants related to beta-cell function, insulin production, insulin sensitivity, and obesity identified by published genome-wide association studies (GWAS) (Aim 3). Dietary insulin demand (assessed by the C-peptide score, insulin index, and insulin load; Aim 4), vigorous physical activity and the macro-level factor of neighborhood built environment (assessed by the county sprawl index, Aim 5). This cost-effective project uses a unique and well-characterized PCa patient cohort of U.S. male physicians with 30 years of complete follow-up for outcomes and assessment of both pre- and post-cancer exposures. Findings of these studies will provide new insights for the role of energy metabolism in PCa progression, guide the identification of novel cancer therapeutic targets, and aid in the development of cancer prevention strategies from urban planning to diet and lifestyle modification.
PI: Jing Ma, M.D., Ph.D., M.P.H.

Impact of Exercise and Metformin on Hyperinsulinemia in Colorectal Cancer Survivors
Observational evidence suggests that factors related to energy balance, including exercise, body weight and diet, may be related not only to the risk of developing colorectal cancer, but also to prognosis in patients who develop the disease. One hypothesis for the impact of these factors on colorectal cancer tumorigenesis and prognosis is related to hyperinsulinemia and insulin-like growth factors. Several studies have demonstrated that colon cancer risk and recurrence rates are elevated in individuals with higher circulating levels of insulin or C-peptide as well as in individuals with higher levels of insulin-like growth factor (IGF)-I or lower levels of IGF binding protein (IGFBP)-3. However, there are no data testing strategies to lower levels of insulin or related hormones in colorectal cancer survivors. Two strategies that have strong scientific rationale to impact on the insulin-related pathways are exercise intervention and metformin. Exercise has consistently been shown in observational studies to reduce the risk of developing colorectal cancer and, more recently, risk of cancer recurrence and colorectal-cancer related mortality. Metformin reduces hyperinsulinemia and activates the AMP-activated protein kinase (AMPK) which suppresses a variety of pathways. In project 4, we propose a 2 x 2 randomized trial of supervised aerobic exercise guided by validated behavioral support techniques versus attention control and metformin versus placebo in stage l-lll colorectal cancer patients within 2 years of completion of therapy. The primary objective will be to determine whether supervised exercise training alone and metformin, either alone or in combination, can decrease fasting insulin level from baseline to 6 months in patients who completed standard therapy for stage I - III colorectal cancer. Secondary objectives include (1) comparing changes in other insulin-related biomarkers, (2) explore for an interaction effect in addition to an additive effect of exercise and metformin in reducing fasting insulin level over the 6 month intervention, (3) compare changes in body composition as well as self-directed change in diet quality, (4) compare changes in pro-inflammatory markers related to insulin resistance, (5) determine whether the theoretical constructs of the theory of planned behavior predict change in exercise behavior.
PI: Jeffrey Meyerhardt, M.D., M.P.H.

University of California, San Diego
Principal Investigator: Ruth Patterson, Ph.D., M.S.
The TREC Research Center at the University of California, San Diego focuses on mechanisms linking obesity with breast cancer risk and conducts studies investigating obesity and lifestyle factors related to insulin resistance and inflammation using mouse models, clinical trials, and wireless and networked technologies in the community.


The overall objective of the UCSD TREC Center is to assemble transdisciplinary scientific collaborators to address questions regarding insulin resistance and inflammation underlying the association of energetics with breast cancer carcinogenesis, from the cell to the community. In Project 1, we will use obese mouse models to investigate whether the beneficial anti-inflammatory and insulin-sensitizing effects of omega 3 fatty acids will reduce breast cancer tumor growth and metastasis and whether the omega 3 fatty acid receptor GPR120 is the critical mediator of those cancer-protective effects. In Project 2, we will conduct a trial in obese women to examine differential response (depending on insulin resistance status) to dietary macronutrient composition. Outcomes will include weight loss, hormonal factors, and markers of inflammation as well as nutrient-gene interactions associated with polymorphisms in IL-6 and TNF-a genes. Project 3 will investigate the degree to which metformin, a lifestyle intervention, or both, can reduce breast cancer mortality among overweight/obese, postmenopausal breast cancer survivors. We will use an innovative Biomarker Bridge design that links clinical outcomes from a breast cancer survivor cohort with intermediate outcomes from a randomized controlled trial. Project 4 will advance the science of energy expenditure estimation by using branched equation modeling techniques and artificial neural networks to analyze accelerometer and heart rate data from participants in Project 2 and 4. Global Positioning System data, which track individuals' spatial-temporal paths, combined with existing Geographic Information Systems data for San Diego County, will allow us to develop obesogenic environmental exposure estimates and relate these to metabolic risk factors. Dr. Patterson, the PI for this proposed Center, has considerable research experience in nutrition and breast cancer prevention and a strong background in leadership and management in academia and industry. The central leadership entity of the UCSD TREC Center will be the Executive Scientific Committee, composed of Project and Core leaders. This Committee, assisted by the Administrative Core, will provide scientific and operational oversight of the Shared Resources (Biostatistics & Bioinformatics and Biorepository) as well as transdisciplinary Training Program and the Developmental and cross-TREC Pilot Project Core. We believe that the TREC Center proposed herein has the potential to make significant contributions to understanding the link between obesity and breast cancer and provide insight regarding interventions with broad population impact for prevention and control of disease.

Role of Inflammation and Insulin Resistance in Mouse Models of Breast Cancer
Obesity confers increased risk for various forms of cancer. Breast, colon, and liver cancer are all increased in obese populations and the epidemiologic evidence for the obesity - breast cancer connection is compelling. One in eight women will be diagnosed with breast cancer during her lifetime. Breast cancer is strongly associated with age as incidence increases 10-fold for women age > 60 compared to women age > 50. Increased risk with age seems related to post-menopausal hormone levels as both obesity and hyperinsulinemia are associated with increased breast cancer risk only in women not on hormone replacement therapy. Metabolic Syndrome is associated with a higher incidence of aggressive triple negative breast tumors (ER-/PR-/HER2-) which is likely accelerated by ovarian hormone decline after menopause, as post-menopausal women are more susceptible to the deleterious metabolic effects of obesity including chronic inflammation and insulin resistance. Rodent studies have confirmed this relationship, showing that diet-induced obesity and high fat diets lead to increased incidence and growth of tumors in various breast cancer models. Despite this body of correlative evidence, the mechanisms of obesity-induced breast cancer risk remain poorly understood. Diet composition is an important factor as diets rich in saturated and omega 6 fatty acids (FAs) are pro-inflammatory and increase breast cancer risk, but diets rich in omega 3 FAs are anti-inflammatory and decrease cancer risk. The clinical data is less clear but meta-analyses of multiple human breast cancer risk studies suggest that the ratio of omega 6 to omega 3 FAs is a critical factor.

We have found that the beneficial anti-inflammatory and insulin-sensitizing effects of omega 3 FAs are mediated by the G-protein coupled receptor GPR120. Due to the potential link between obesity, insulin resistance and breast cancer risk in post-menopausal women, we hypothesize that GPR120 is the critical mediator of the protective effects of omega 3 FAs in breast cancer. We will test this in four specific aims that combine 1) studies using orthotopic tumor cell transplants and 2) spontaneous tumors in obese wild type (WT) and GPR120 knockout (KO) mice, ± omega 3 FA supplementation, 3) studies using orthotopic mouse and human tumor cell transplants into RAG2 KO mice, and 4) studies of metastasis using genetically marked tumor cells in obese WT and GPR120 KO mice. We hypothesize that omega 3 FAs will attenuate tumorigenesis and metastasis in WT but not GPR120 KO mice through their anti-inflammatory/insulin-sensitizing actions. This project aims to provide mechanistic depth that is complementary to aims of Projects 2 & 3.
PI: Jerrold Olefsky, M.D.

Diet Composition and Genetics: Effects on Weight, Inflammation, and Biomarkers
Excess adiposity is a risk factor for postmenopausal breast cancer and a major risk factor for recurrence in both pre- and postmenopausal breast cancer, and the biological mechanisms are not fully understood. Obesity is associated with elevated endogenous circulating estrogen as well as activation of the immune system, a key causative factor in insulin resistance and hyperinsulinemia. Optimal macronutrient distribution of weight loss diets has not been established. Cancer control guidelines have historically encouraged a low fat diets, but current evidence does not suggest this strategy to be of particular benefit. Emerging evidence suggests that the optimal diet composition for weight loss may differ across individuals based on metabolic status and genetic factors. Effects of diet composition on hormonal and other factors linking obesity to breast cancer in weight loss interventions have not been compared or examined. The specific aims of this study are: (1) To examine whether there is a differential weight loss response to different dietary macronutrient composition in weight loss intervention in healthy obese women, depending on insulin resistance status; (2) To examine whether there is a differential response (depending on insulin resistance status) to different dietary macronutrient composition in a weight loss intervention in the hormonal factors and markers of inflammation that may link obesity to breast cancer mortality (insulin, SHBG, estrogens, C-reactive protein, interleukin-6 [IL-6], tumor necrosis factor a [TNF-a], and as a marker for gene expression, IL-6 and TNF-a gene methylation); and (3) To identify nutrient-gene interactions that contribute to differential response of cytokines to weight loss and diet composition associated with polymorphisms in IL-6 and TNF-a genes. These aims will be addressed in a randomized controlled study involving 156 obese women randomly assigned to a high-carbohydrate (65% energy) low-fat (20% energy) or low-carbohydrate (45% energy) high monounsaturated fat (35% energy) diet in a 12-month behavioral weight loss program. We hypothesize that greater weight loss and reduction in biomarkers will occur in insulin resistant women assigned to the lower carbohydrate, higher fat diet. We also hypothesize that the ability of weight loss and diet modification to decrease IL-6 and TNF-a concentrations will be influenced by polymorphisms in these genes. Results of this study will help to refine and individualize dietary guidance for optimal weight control and breast cancer prevention and will contribute to knowledge of mechanisms that link insulin resistance, inflammation and obesity to risk and progression of breast cancer.
PI: Cheryl Rock, Ph.D.

Obesity-related Mechanisms and Mortality in Breast Cancer Survivors
The objective of this proposed study is to investigate the degree to which metformin, a lifestyle intervention, or both, can reduce breast cancer mortality among overweight/obese, postmenopausal breast cancer survivors. We will use a "Biomarker Bridge" design that links clinical outcomes from a breast cancer survivor cohort with intermediate outcomes from a randomized controlled trial by means of a Biomarker Risk Score. Biomarker Risk Score Development: We will assay panels of interrelated biomarkers in 375 archived blood samples obtained from overweight/obese, postmenopausal women with a history of breast cancer (125 cases [breast cancer death]:250 matched controls). These Biomarkers represent proposed mechanisms by which obesity is associated with postmenopausal breast cancer: (1) alterations in the insulin-IGF axis, (2) concentrations of endogenous sex hormones, and (3) chronic inflammation. We will identify a set of markers that best predicts breast cancer mortality using conditional logistic regression models adjusted for prognostic factors. This model (i.e., Biomarker Risk Score) measures the log-odds of disease risk due to joint biomarker concentrations. Therefore this Risk Score can measure changes in log-odds due to changes in these markers in an individual and will be used to assess the clinical impact of the metformin and lifestyle intervention randomized trial. Metformin/Lifestyle Intervention Trial: We will conduct a 6-month, randomized controlled trial in 340 overweight/obese, postmenopausal breast cancer survivors. Participants will be randomized in equal numbers to (1) placebo, (2) metformin, (3) lifestyle intervention and placebo, or (4) lifestyle intervention and metformin. The lifestyle intervention will focus on reducing energy intake and increasing energy expenditure to achieve a 7% weight reduction. Biomarkers that compose the Risk Score will be assayed in fasting blood samples collected at baseline and 6 months. The degree to which each intervention changes (e.g., reduces) the Biomarker Risk Score will be used to predict changes (e.g. reductions) in breast cancer mortality. We hypothesize that metformin and lifestyle interventions will reduce breast cancer mortality and that the combination of those interventions will have an additive effect on lowering risk. In summary, this Biomarker Bridge Design will (i) develop a Biomarker Risk Score that predicts breast cancer mortality, (ii) examine how a metformin/lifestyle intervention changes this Risk Score, and (iii) thereby assess the degree to which metformin and lifestyle interventions influence the biological processes linking obesity with breast cancer mortality.
PI: Ruth Patterson, Ph.D.

Assessment of Energy Expenditure in Women with Increased Cancer Risk
Energy expenditure is a key component of energetics, and physical activity comprises the largest modifiable component of energy expenditure. Energy expenditure and physical activity are strongly related to Insulin resistance and other markers of glycemic control important for cancer risk. Sedentary behavior has also recently emerged as an independent predictor of metabolic risk, and temporal analyses of objective sedentary behavior data have indicated that breaks in sitting time may be a critical intervention strategy to complement improvements in moderate to vigorous physical activity. In the last decade, the impact of the built environment has also been assessed in relation to physical activity, sedentary behavior and weight status. This research, however, has focused on a static view of residential neighborhoods which may be confounding the relationship between health and place. We propose to advance the field of energy expenditure, physical activity, and sedentary behavior assessment across the cancer continuum by improving the accuracy of energy expenditure-related assessments in our TREC projects #2 and #3. We will use state of the art accelerometers with simultaneous heart rate recording to improve the accuracy of measuring physical activity, sedentary behavior, and energy expenditure. In addition to branched equation modeling techniques we will also use new computational approaches for analyzing data streams from these devices, including artificial neural networks that allow combining these data to decipher the frequency, intensity, duration, and type of physical activity and sedentary behavior so as to optimally characterize behaviors of study participants and reduce the measurement noise in observed relationships between these behaviors and markers of glycemic control. Finally, data from Global Positioning System devices that track the temporal and spatial movements of participants will be combined with existing Geographic Information Systems data for San Diego County to allow us to develop obesogenic environmental exposure estimates and relate these to the metabolic risk factors. These data will be processed through software developed by our group under the NIH Gene & Environment Initiative. This will enable us to use novel computational techniques to assess the relationships over time and across the study arms between energy expenditure, physical activity and sedentary behavior and metabolic risk factors related to breast cancer measured in Projects #2 and #3 as well as the moderating effect of exposure to obesogenic environments.
PI: Jacqueline Kerr, Ph.D.

University of Pennsylvania
Principal Investigator: Kathryn Schmitz, Ph.D., M.P.H.
The University of Pennsylvania TREC Research Center focuses on the association between energy balance and breast cancer recurrence and persistent adverse treatments effects and explores the impact of exercise and weight control interventions in cancer survivors through cost effectiveness analysis.


The overall goal of the Penn TREC Survivor Center is to improve the length and quality of cancer survivorship through establishing a sustainable transdisciplinary research, education, and outreach program that extends from 'bench to trench'. The proposed center will enhance knowledge of the causal associations of energy balance and breast cancer recurrence, from animal to human models, as well as exploring and integrating this knowledge with broad population impact at the policy level for control of obesity related adverse events among cancer survivors. Three projects are proposed. Project 1 will explore whether exercise and/or weight loss will alter breast cancer recurrence in mice and explore effects on biomarkers of mechanistic pathways hypothesized to explain these effects. Project 2 will translate project 1 biomarker findings into a human model. Intervention effects on clinical lymphedema outcomes will also be assessed in Project 2. Project 3 will assess whether exercise and/or weight loss is cost effective for breast cancer survivors with lymphedema. Organizationally, the administrative core will serve as the glue between the investigators, so that as the projects, training activities, and developmental pilots unfold, the transdisciplinary, translational nature of the center is preserved and extended. The developmental core will accelerate capacity to study effects of energetics on cancer recurrence by combining the unique strengths of our institution in obesity and cancer biology and extending the TREC initiative solidly into cancer survivorship. The education/training and outreach core will train scientists and clinicians regarding energy balance and cancer survivorship, service the dual purpose of educating health care providers regarding the unique energy balance issues in survivors and spurring interest in research on this growing population across the spectrum from basic science to clinical applications. The Penn TREC Survivor Center will leverage the considerable strengths of Penn scientific investigators and physician scientists to accelerate capacity for research on energetics, cancer recurrence and persistent adverse treatment effects as well as disseminating those findings to improve clinical care and outcomes for cancer survivors.

Impact of Exercise and Caloric Restriction on Cancer Recurrence in Mice
Understanding the biological mechanisms that underlie the anti-tumorigenic effects of calorie restriction and physical activity will likely be essential for translating laboratory advances in this field to the development of more effective strategies for preventing cancer in humans. The goal of Project 1 of the Penn TREC Survivor Center is to advance our understanding of the impact of Energetics on breast cancer recurrence. Project 1 will use an innovative genetically engineered mouse model for breast cancer recurrence developed at Penn to determine the effects of exercise, calorie restriction, or their combination on breast cancer recurrence. Mammary tumors will be induced in overweight mice by the doxycycline-dependent activation of an oncogene relevant to human breast cancer in the mammary glands of mice fed a high fat diet. Regression of the resulting tumors will be induced by oncogene down-regulation to generate cohorts of mice bearing dormant residual tumor cells. Overweight mice bearing residual disease will be randomly assigned to exercise, calorie restriction, both of these interventions, or neither and followed for cancer recurrence. Biomarkers will be evaluated to explore the hypothesized relationship between energy balance and recurrence and will include markers reflecting the PI3K-Akt-mT0R pathway, insulin resistance, IGF-1, HGF, adipokines, inflammation, tumor angiogenesis and oxidative stress. To our knowledge, this study will be the first to explore the impact of exercise and calorie restriction on cancer recurrence in an animal model. The studies proposed in Project 1 build on the unique combination of strengths and expertise in cancer biology, obesity, endocrinology, and exercise physiology among researchers in the proposed Penn TREC Survivor Center. In addition, the design of this study closely parallels an analogous human trial proposed in Project 2. The assembled team of investigators will work jointly to create new experimental paradigms that integrate and move beyond discipline-specific approaches to address the role of energy balance in breast cancer recurrence. In doing so, this project will advance the mission of the Penn TREC Survivor center to promote transdisciplinary, translational science on energy balance and cancer survivorship.
PI: Lewis Chodosh, M.D., Ph.D.

Women in Steady Exercise Research (WISER) Survivor Trial
Breast cancer survivors face dual challenges: 1) risk of recurrent disease and 2) dealing with the long term sequelae of their treatments. Facing these challenges can be burdensome, resulting in reduced quality of life. Obesity and sedentary lifestyle further complicate these issues. The goal of the WISER Survivor trial is to assess the effects of exercise and/or weight loss through caloric restriction on a common long term adverse effect of treatment (lymphedema), biomarkers for recurrence, and quality of life.

Lymphedema is a chronic, progressive, incurable condition characterized by arm swelling and negative alterations in function and appearance, as well as bothersome symptoms. It is among the more common, expensive, and feared persistent adverse breast cancer treatment effects. In our completed work, twice weekly weight-lifting reduced by half the number of incident clinical lymphedema events requiring medical care. In the proposed WISER Survivor trial we seek to assess whether adding aerobic exercise or weight loss through caloric restriction to the weight-lifting intervention further improves lymphedema clinical outcomes.

The WISER Survivor Trial will also test the effects of the exercise and weight loss interventions on the same recurrence biomarkers to be tested in the mouse model study (Project 1). The biomarkers include sex hormones, markers of inflammation, growth factors, adipokines, and oxidative stress. The innovation of these two paired projects include the novel approach of assessing effects of these interventions in the recurrence setting, as well as comparing effects on biomarkers in equivalent interventions in mice and humans. In addition, we assess effects of our energy balance interventions on a novel biomarker related to pathogenic angiogenesis. Another innovation includes a unique opportunity to assess whether changes in any of these biomarkers are correlated with clinical lymphedema outcomes. Finally, we seek to assess effects of our interventions on quality of life in breast cancer survivors with lymphedema.

Therefore, we propose a one year randomized controlled weight loss and exercise intervention trial in a multi-ethnic cohort of overweight and obese post-menopausal breast cancer survivors with clinically confirmed lymphedema. There will be four groups in this trial: exercise only, weight loss only, exercise and weight-loss combined, and a control group, with a sample size of 125 per group (total N=500).
PI: Kathryn Schmitz, Ph.D., M.P.H.

Breast Cancer-Related Lymphedema: Cost of Illness and Cost Effectiveness of Alternative Management Strategies
Breast cancer related lymphedema (BCRL), characterized by arm swelling, impaired function and bothersome symptoms, is a common, persistent, often progressive adverse event of breast cancer diagnosis and therapy, exacerbated by obesity and sedentary lifestyle. The WISER Survivor Trial (Project 2) will assess in a multi-ethnic cohort of overweight and obese post-menopausal women with BCRL the incremental clinical effectiveness (lymphedema flares, cellulitis, quality of life) of exercise only, weight loss only, and exercise and weight-loss combined compared with a usual care control group.

While BCRL incurs substantial health care costs (significant portions of which are borne by patients), reduces productivity and reduces quality of life, empirical data are sparse. Effective behavioral interventions such as exercise training and weight loss that temporize BCRL, mitigate its impact and prevent progression often are not reimbursed; third party payers rarely cover supplies required to mitigate BCRL. As a consequence, the current insurance structure perversely places breast cancer survivors at needless risk of BCRL adverse events and sequellae and may increase costs as a result of increased downstream complications (e.g., outpatient care and hospitalizations for repeated episodic lymphangitis and cellulitis; physical therapy for BRCL flares and symptomatic exacerbations). Thus, there is a compelling need to better characterize the medical economic impact of BCRL, as well as its short- and long-term health consequences.

Project 3 will; (1) assess BCRL direct medical care costs; (2) assess the incremental cost-effectiveness of the Project 2 WISER Survivor interventions; and (3) model the impact of the WISER Survivor interventions over an extended time frame. The novel methodological approaches developed to define and identify BCRL cases combining and integrating data from patient reports, administrative claims and national language queries of electronic medical records will inform criteria to identify and select BCRL patients for future studies, as well as establish the validity of alternative methods, while demonstrating the feasibility and potential value of this approach for other medical conditions.
PI: J Sanford Schwartz, M.D.

Washington University in St. Louis
Principal Investigator: Graham Colditz, M.D., Dr.P.H.
The TREC Research Center at Washington University in St. Louis uses multilevel and multigenerational approaches to investigate mechanisms by which preconception diet, nutrition and built environment policies impact inactivity and how physical activity and energy balance influence body weight and carcinogenesis across the lifespan.


Drawing on the broad scientific expertise of faculty at WUSTL, and collaborators and consultants from other institutions, we propose to build on existing transdisciplinary approaches and create a center to address mechanisms of obesity and cancer, "from cell to society". We include projects that move beyond traditional risk factor-cancer associations to look at multilevel and multigenerational associations as well as the interaction of traditional cancer risk behaviors. We leverage the unique opportunity Missouri provides to study human populations given its diversity across race/ethnicity and socioeconomic status. We will delineate mechanisms by which preconception diet, nutrition and built environment policies impact inactivity and how physical activity and energy balance influence body weight and carcinogenesis across the lifecourse. Specifically we aim to:
1. Investigate in a mouse model the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in male mouse offspring;
2. Study the role of physical activity and obesity in post-prostatectomy urinary and sexual function;
3. Develop models of obesity across the life course and generations incorporating biologic, clinical and social determinants of risk and mortality, which can be applied to different cancer outcomes, using non-Hodgkin Lymphoma as the initial platform;
4. Study policies relating to nutrition and built environment that impact energy balance and obesity;
5. Train postdoctoral fellows in a transdisciplinary environment to pursue careers in energetics and cancer and expose scholars from across our university to transdisciplinary work in obesity and cancer;
6. Foster scientific synergy via smaller-scale innovative transdisciplinary research that builds on the Center's theme and resources; and
7. Maximize efficiency and productivity of TREC-related studies and cores by building an outstanding transdisciplinary center supported by outstanding administrative, budgetary, and technology resources.

To address these aims, we propose four research projects and five cores that form a cohesive, transdisciplinary center focused on research, training/career development, and dissemination.

Transgenerational Animal Models of Nutritional Impact on Cancer Predisposition
The objective of the current study is to investigate the effect of maternal high fat diet and changes in metabolic bioenergetics on prostate gland development and susceptibility to prostate cancer in the male offspring. We hypothesize that a high fat maternal diet prior to and throughout pregnancy alters epigenomic marks leading to abnormal expression of key genes involved in the development of the prostate gland, which predispose the offspring to develop prostate cancer. Our rationale is that if maternal diet and metabolic bioenergetics alter the process of tumor development and progression in the prostate, then further studies exploring the mechanism of this process may elucidate new therapies and recommendations for the prevention and treatment of prostate cancer. To test our hypothesis the following aims will be pursued: Specific Aim 1: To examine prostate gland development and imprinted gene expression in control vs. high fat fed offspring, from mothers given a high fat diet for 1 month prior to conception and throughout pregnancy. Specific Aim 2: To examine the incidence and timing of tumor development in offspring of control vs. high fat fed mothers by administration of diethylstilbestrol (DES) to neonatal male mice on postnatal days 1-5. Specific Aim 3: To examine the effects of a high fat diet on tumor development in an established model for prostate cancers. The high fat diet experiment will be performed in mice with prostate specific knockout of PTEN vs. controls (Ptenloxp/loxp;PB-Cre4+) vs Pten+/+;PB-Cre4-).

This proposal is innovative in that although data show that dietary changes during pregnancy can result in epigenetic changes in the offspring and that some of these epigenetic changes have been linked to prostate cancer, the connection between maternal diet and prostate cancer has never been explored. It is anticipated that the maternal diet of high fat will accelerate this process and decrease the latency period to the development of cancer. If successful in completing our aims this work will advance our understanding of how changes in maternal diet and metabolic bioenergetics in utero have transgenerational effects on the predisposition and development of prostate cancer.
PI: Kelle Moley, M.D.

Prostatectomy, Incontinence and Erectile function (PIE)
Using supplemental data collection in two ongoing cohort studies, we will examine whether physical activity and obesity, individually and jointly, influence sexual and urinary function outcomes in men with clinically localized prostate cancer undergoing radical prostatectomy. We will explore whether these associations vary by race. Finally, we will investigate whether post-surgical change in physical activity and weight are associated with urinary and sexual function.

Aim 1: To determine the independent associations of pre-surgical physical activity and BMI with postprostatectomy urinary and sexual function.

Aim 2: To explore the additive and multiplicative effects of physical activity and BMI on sexual and urinary function.

Secondary Aim 1: To help inform potential future interventions, we will examine the effect of change in physical activity and BMI from pre-treatment to 12 months post surgery on urinary and sexual function.

Secondary aim 2: To explore whether the hypothesized effect of physical activity and BMI on urinary and sexual function differs by race.
PI: Graham Colditz, M.D., Dr.P.H. and Adam Kibel, M.D.

Worksite Policies and Neighborhood Influences on Obesity and Cancer Risk
Up to 30% of all cancer deaths in the United Slates may be attributable to obesity. Environmental and policy supports for physical activity and healthy eating represent promising strategies to curb the rise in obesity rates and related cancers. Mounting research suggests that the built environment can facilitate or constrain physical activity and healthy eating, particularly for low-income and minority populations. However, virtually all of this research has examined environmental influences among residential settings, disregarding the work environment where employed adults spend much of their time. The overall goal of this project is to understand how environments and policies where employed adults live and work are associated with obesity. This goal will be accomplished by addressing the following aims: (1) Develop and test the reliability and validity of self-reported instruments for assessing worksite environments and policies relevant for physical activity and diet behaviors; (2) Examine whether specific types and number of worksite supports for physical activity and healthy eating are predictive of obesity; (3) Examine whether perceived and objectively measured characteristics of the built environment in the residential and worksite neighborhood are independently and jointly associated with body mass index (BMI); and (4) Disseminate findings to local worksites, governments, and practitioners. Employed adults (n=2000) will be sampled among randomly selected census tracts in four metropolitan areas in Missouri, with oversampling of high racial/ethnic minority and high population density census tracts. Data on self-reported behaviors, BMI, and perceived environmental and organizational supports for physical activity and healthy eating will be derived from a targeted random-digit-dial telephone survey. Accelerometry will be collected on a sub-sample of the study population. Participants' data will be linked with contextual poverty, environmental and policy data derived using Geographic Information Systems, and multilevel modeling will be used to analyze the nested data. Findings will be disseminated among urban planners, employers, and policymakers to encourage the translation of evidence into practice and policies.
PI: James Aaron Hipp, Ph.D., B.S. and Ross Brownson, Ph.D.

Social Determinants in the Link between Obesity and Cancer
Project 4 will focus on understanding the role that social determinants play in the link between obesity and cancer at the population level across the lifespan by developing a multi-cohort simulation model of obesity and non-Hodgkin's lymphoma (NHL).

Aim 1: Develop a multi-cohort system dynamics computer simulation model of obesity and NHL population level incidence, treatment toxicity and survival trends. This will extend the obesity modeling from childhood to adult populations, develop a population level model of NHL, and based on emerging individual level analysis from the VHA cancer registry database, integrate these two models over the life course.

Aim 2: Analyze the resulting model to identify how social determinants influence obesity and NHL population level incidence and outcome trends. This analysis will identify dominant social determinants, delayed effects, and temporal relationships across the life course.

Aim 3: Design guidelines along with their implementation strategies to identify the most effective way to reduce the impact of social determinants of NHL population level outcomes. This will generate different guidelines (e.g., policy, prevention, screening, treatment, and survivorship care) along with potential implementation strategies to determine the best combination of guideline-implementation strategy for reducing the burden of NHL.

This project is transdisciplinary. It will complement existing and separately funded work to develop an innovative system dynamics model of childhood obesity by extending the model into adulthood across the lifespan and develop a NHL model that will be combined with the extended obesity model. Once established, additional cancers can be added to the model from this or other TRECs.

This project is significant. It will not only provide rigorous conceptual models of how social determinants for obesity and NHL might interact over time, but also help identify key areas for future transdisciplinary research that have high potential for population level impact. Involvement of the expert panel in the modeling process will facilitate the development of transdisciplinary knowledge. The model will also be one of the first to link efforts from the NIH funded Cancer Intervention and Surveillance Modeling Network (CISNET) and the NIH/RWJF funded Comparative Modeling (CompMod) Network for obesity prevention.
PI: Peter Hovmand, Ph.D., M.S.W. and Graham Colditz, M.D., Dr.P.H.

Coordination Center

Coordination Center (FHCRC)
Principal Investigator: Mark Thornquist, Ph.D.
The TREC Coordination Center at Fred Hutchinson Cancer Research Center integrates efforts across the network of individual TREC Research Centers and facilitates transdisciplinary research by supporting communication, scientific collaboration, logistical infrastructure for data management and bioinformatics, results dissemination, training, and evaluation.


The two goals of the TREC initiative are: 1) enhance knowledge of the current mechanisms underlying the association between energy balance and carcinogenesis, and 2) explore and integrate the etiology of obesity behavior and relevant health behavior theories, with broad population impact at the social-environmental and policy levels for prevention and control of obesity, focusing on children, groups at high risk for obesity, and cancer survivors. The overall aims of this application for the TREC Coordinating Center are to: 1) facilitate transdisciplinary research through scientific leadership and organizational support with emphasis on efficient communication, coordination of efforts, and expanded scientific collaboration across multiple research institutions; 2) facilitate contacts between TREC awardees and NCI professional staff to allow for efficient interactions, consultations, and oversight functions; 3) create significant new opportunities for transdisciplinary training of scientists at every stage in their careers in the area of energetics and cancer; 4) create and manage relevant logistical infrastructure (including research data management and bioinformatics) to support the TREC Research Centers; 5) create opportunities to disseminate results across multiple venues; and 6) in collaboration with the NCI and the TREC Research Centers, facilitate integration and evaluation of TREC. Under the direction of the TREC Steering Committee, the TREC CC will 1) perform consortium coordination by providing support for TREC meetings and workshops, developing and maintaining TREC secure and public websites and electronic mailing lists, and producing and maintaining TREC documents; 2) support TREC collaborative studies by developing and maintaining collaborative study data management systems; 3) work with the NCI and the Steering Committee on evaluating TREC centers and providing them constructive feedback; 5) work with the NCI and the Steering Committee to provide informatic resources for the sharing and dissemination of documentation and data; and 6) develop a training program to produce more transdisciplinary researchers.