“Influence of Obesity and Metformin Use on the Transformation of Monoclonal Gammopathy of Undetermined Significance into Multiple Myeloma

Principal Investigator
Su-Hsin Chang, PhD, assistant professor, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine

Co-Principal Investigator
Ken Carson, MD, assistant professor, Medical Oncology Section, Division of Oncology, Department of Medicine, Washington University School of Medicine

Project Summary
Multiple myeloma (MM) is the second most common hematologic malignancy in the United States, with 20,000 new diagnoses annually. There is no cure for MM, and the only known modifiable risk factor for the development of MM is obesity. All MM is preceded by a pre-malignant condition known as monoclonalgammopathy of undetermined significance (MGUS). The annual risk of transformation of MGUS to MM is ~1% with roughly a 25% risk of transformation over a lifetime. Approximately 3% of the population over age 50 has asymptomatic MGUS. Hypothesized mechanisms for the progression of MGUS to MM include stimulation of the insulin-like growth factor receptor pathway by insulin. Therefore, it is conceivable that an agent that decreases insulin production, such as metformin, could alter the progression of MGUS to MM, particularly in obese patients. Furthermore, metformin has been associated with a reduced risk of breast cancer development in women with diabetes mellitus, suggesting it may inhibit carcinogenesis for some diseases. Enhanced understanding of the influence of obesity on the development of MM in patients with MGUS as well as the influence of metformin on this process would suggest new opportunities for the development of lifestyle, surgical, and/or pharmacologic interventions to reduce the incidence of MM. We plan to develop a cohort of patients with MGUS from the United States Veterans Health Administration hospital system to evaluate questions related to obesity, metformin use, and progression of MGUS to MM. To account for the potential confounding and bias arising in the data, we propose to use econometric methods to study the following aims.

Project Aims

  1. Use mixed proportional hazards modeling to determine if overweight or obesity is associated with an increased risk of progression of MGUS to MM in veterans diagnosed with MGUS.
  2. Use propensity score analysis to determine if metformin decreases the risk of progression of MGUS to MM.

“Interaction of Dietary Fat and Fatty Acid Trafficking on Intestinal Polyp Formation”

Principal Investigator
Sekhar Dharmarajan, MD, St. Louis VA Hospital

Nicholas Davidson, MD, DSc, chief, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine

Project Summary

Colorectal cancer (CRC) is the third most prevalent cancer and second-leading cause of cancer death in the United States. While genetic factors play a key role in the pathogenesis of CRC, environmental modifiers and gene-environment interactions have a significant influence on susceptibility to CRC. Two of the more well-studied environmental modifiers are excessive dietary fat intake and obesity, which both significantly increase the risk of CRC development. These observations have increased attention to the role of fatty acid (FA) metabolism in CRC and suggest that intestinal processing and metabolism of fatty acids (FA) trigger pathways that modulate tumorigenesis. Liver fatty acid binding protein (L-Fabp) is the dominant intestinal fatty acid binding protein and is abundantly expressed in small intestine and colon. L-Fabp is a cytosolic lipid chaperone protein that acts as a metabolic sensor by trafficking and compartmentalizing fatty acids along different signaling pathways via nuclear hormone receptors, a family of transcription factors involved in regulating gene expression in response to nutritional and metabolic stimuli. Studies in a novel line of LFabp knockout mice reveal a dramatic phenotype with protection against dietary fat-induced obesity on a high saturated fat diet, but not on a high polyunsaturated fat diet. The overarching hypothesis of this project is that L-Fabp alters the trafficking and metabolism of essential dietary fatty acids which thereby modulates different signaling pathways that govern intestinal tumor initiation and progression. This project will examine the susceptibility of L-Fabp knockout mice to intestinal tumorigenesis when alterating dietary fat intake in a relevant preclinical murine model of tumorigenesis, the Apc min model, a genetic model of intestinal neoplasia. On the basis of preliminary data, it is predicted that L-Fabp knockout mice will be protected against the development of intestinal tumorigenesis on a high saturated fat, but not on a high polyunsaturated fat diet. We will utilize the novel technology of lipidomics to assess the effect of dietary fat intake on intestinal tumor formation. These studies should lead to greater insight into the mechanisms by which FA metabolism influences intestinal tumorigenesis.

Project Aims

  1. To determine the effect of diet supplementation with SFAs and PUFAs on intestinal polyp formation in mice with a germline deletion of L-Fabp in the ApcMin/+ model, a genetic model of intestinal neoplasia.
  2. To identify differences in lipid profiles in serum and intestinal tumors from ApcMin/+ and LFabp–/–Apcmin/+ mice on high SF and PUFA diets using metabolomic and lipidomic analyses.

“A Worksite Intervention to Promote Health in Public Utility Workers”

Principal Investigator
Rachel Tabak, PhD, research assistant professor, Prevention Research Center, George Warren Brown School of Social Work

Project Summary
Unhealthy lifestyle behaviors related to nutrition, energetics, energy balance, obesity, and physical activity are major contributors to cancer and other chronic conditions. Employers have a vested interest in these behaviors as providers of health insurance for over 160 million workers and their families. However, it is difficult to conduct worksite wellness research with adequate scientific rigor and to evaluate sustainability. We will design and determine the effectiveness and sustainability of a broad program to be introduced by Ameren, a public utility headquartered in St. Louis that employs 9,000 people. Ameren has eight plants, nearly identical in mission (coal-fired energy production) and employee composition, employing 200 to 400 individuals at each plant. This project provides a unique opportunity to gain valuable information on interventions for addressing cancer prevention. However, intervention impact will be sub-optimal if the intervention is not tailored to the population and its values. In this study, this will be accomplished through key information interviews with plant-based nurses and human resources/wellness staff; focus group discussions with workers and managers; a lunch inventory; and a survey of current environment and policies based on the survey developed for the SHOW-ME Study (TREC@WUSTL main project #3). The deployment of Ameren’s workforce among eight plants provides the opportunity for a controlled, randomized intervention approach, but also demands a carefully crafted, complex formative process – including time and effort consuming steps requiring the determination of plant-level organizational characteristics and worker and management interests, values, and priorities. The partnership with Ameren also allows for analysis of insurance claims data to focus the intervention on the top healthcare needs and to provide baseline costs. This work will lead directly to development of an optimized intervention and grant proposal for future intervention studies in this population and translation of our findings to other worksite settings.

Project Aim
Systematically understand the needs, attitudes and values, as they relate to nutrition, energetics, energy balance, obesity, and physical activity among Ameren employees, the relevant stakeholders.