Mechanisms that Impact Cancer Risk after Bariatric Surgery (R01 Clinical Trial Optional)

Through this Funding Opportunity Announcement (FOA), the National Cancer Institute (NCI) invites applications for support of investigator-initiated studies addressing mechanisms by which bariatric surgery impacts cancer risk, and seeks to draw in talented scientists who study bariatric surgery to investigate its effects on cancer, rather than shorter-term outcomes such as weight loss and diabetes.Through this Funding Opportunity Announcement (FOA), the National Cancer Institute (NCI) invites applications for support of investigator-initiated studies addressing mechanisms by which bariatric surgery impacts cancer risk, and seeks to draw in talented scientists who study bariatric surgery to investigate its effects on cancer, rather than shorter-term outcomes such as weight loss and diabetes. Background Obesity: Obesity will soon surpass smoking tobacco as the number one cause of preventable death both in the United States and worldwide. Bariatric (metabolic) surgery is the most effective strategy to achieve significant initial and sustained weight loss among individuals who are morbidly obese. Bariatric surgery provides dramatic improvement in metabolic function, associated with a reduction in type 2 diabetes mellitus (T2DM) and cardiovascular (CV) risk. Bariatric surgery also appears to reduce the risk of certain obesity-related cancers, although which cancers are favorably impacted vary by study, and the mechanism(s) driving this risk reduction is mostly speculative. Bariatric surgery is performed in over 250,000 people in the U.S. annually, and the frequency is rising. Studies evaluating which bariatric surgery procedure(s) are most effective in cancer risk reduction could help bring to light new pathways to target for cancer prevention. Bariatric Surgery: Importantly, it is not yet clear from clinical and preclinical studies if the benefit from bariatric surgery arises from weight loss alone or if there is also a surgery-specific benefit. One mechanism for a possible surgery-specific effect is elevated bile acids (BA), both intestinal and circulating, after gastric bypass surgery such as Roux-en-Y gastric bypass (RYGB) that are proposed to be central to weight loss and other metabolic benefits. The interaction between BA and intestinal microbes is also an area of intense interest. Studies have identified important changes after bariatric surgery in the composition and function of the gut microbiome, which may mediate bariatric surgery effects. Fecal microbiota transplantation (FMT) from humans or mice that had undergone bariatric surgery to germ-free recipient mice showed decreased weight gain and decreased adiposity are both transmissible traits. In addition, FMT induced important host metabolic changes including decreased energy harvest from the diet, increased resting energy expenditure, and increased lipid utilization. The data suggest a causal link between gut microbiota and the metabolic and weight loss effects of bariatric surgery. If validated, the findings will provide insight into the mechanisms driving the benefit of bariatric surgery on cancer risk and would be useful to further scientific understanding and patient care. Animal Models: Several diets or genetically induced animal models of obesity have consistently demonstrated the benefits of weight loss on cancer risk, and these obesity-induced tumor models may be adaptable to bariatric surgery studies, such as the Kras model of pancreatic cancer. Animal models have been developed to study the effects of bariatric surgery. Rodent animal models are most often used due to feasibility (low cost, ease of housing) and have been used extensively to study the mechanism(s) of bariatric surgery responsible for the reduction or elimination of T2DM and CV risk. However, very little has been reported on bariatric surgery and cancer risk despite the fact that both rat and murine models of mammary and other cancers develop in 6 months or less, making it feasible to assess mechanistic changes that influence cancer risk. Bariatric Surgery and Cancer Risk: Obese patients undergo bariatric surgery for a variety of reasons, including weight loss and improvement in metabolic dysfunction. Physician advice regarding the potential benefit of bariatric surgery and cancer risk reduction can currently only be given in generalities based on large-scale studies and not targeted to the individual. Many but not all bariatric surgery investigations document an overall cancer risk reduction among women but not men. Some but not all bariatric surgery studies have found that both women and men undergoing bariatric surgery have an increased risk of colorectal cancer (CRC). Older studies which assessed bariatric surgery and cancer risk may not be useful to guide targeted advice to patients, as one of the most common procedures performed in the past, gastric banding, is only performed in 1% of bariatric surgery procedures today. The two most common bariatric surgery procedures currently performed are sleeve gastrectomy and RYGB. As such, planned animal and/or human studies should focus on the mechanistic effects of the two procedures that are currently in common use. Human biospecimens and/or data may be available from cohorts to enhance the studies proposed including the Longitudinal Assessment of Bariatric Surgery (LABS), Adolescent Bariatrics: Assessing Health Benefits & Risks (Teen-LABS), and NCI Cohort Consortium Members. Applications that include collaborators from fields outside of cancer research will be given special programmatic consideration. Responsive applications may investigate animal models, human studies, or a combination of both. General Area of Research and Scope of Work for this FOA General Area of Research Examples of relevant areas of research include but are not limited to: Do alterations in cancer risk biomarkers occur before weight loss? If so, in what organ, tissue, or cell type do they originate? Is maximum weight loss or long-term weight loss more important for cancer risk reduction? If so, how do the two differ at a cellular and/or biochemical level? What mechanism(s) explain the evidence that bariatric surgery is more beneficial in cancer risk reduction in women than men? Does bariatric surgery increase or decrease the risk of CRC, and if so, what are the mechanism(s)? Which cancers are decreased in incidence by bariatric surgery, and what are the mechanism(s) that explain the effect? Are any cancers increased in incidence by bariatric surgery? If so, through what mechanism(s)? Does the specific bariatric surgery procedure have an impact on cancer risk? If so, what are the mechanism(s) driving the difference in impact? Does racial or ethnic background influence the impact of bariatric surgery on cancer risk, and if so, what are the mechanism(s) involved? How does bariatric surgery affect the penetrance of high-risk genetic predisposition to cancer? Scope of Work and Additional Guidance It is anticipated that studies will evaluate bariatric surgery animal models where a significant proportion of the animals develop cancer. Similarly, human studies involving individuals who will or have undergone bariatric surgery are also encouraged, so long as within the cohort to be studied the number of enrolled subjects who develop cancer is adequate to for a statistically powered endpoint linking cancer (and not a biomarker of cancer) to a molecular mechanism as the driver of cancer. When appropriate and feasible, the investigators may want to evaluate mechanisms influenced by bariatric surgery in animal models of cancer and evaluate potential changes that might correlate with humans due to bariatric surgery. We define mechanism as a biologic endpoint based on analyzed samples from bariatric surgery animal models or from subjects who have or are planned to undergo bariatric surgery. This FOA does not support studies where an epidemiologic endpoint is the primary aim of the project. The mechanism(s) to be studied should evaluate samples collected from animals or humans who have undergone bariatric surgery who did or did not develop cancer. If both animals and humans are studied, the mechanisms chosen should be based on a cancer endpoint. Applications Not Responsive to This FOA The following types of activities remain outside the scope of this FOA, and applications proposing them are non-responsive to this FOA and will not be reviewed. This FOA is not intended for epidemiologic studies, where the primary endpoint is the assessment of cancer in a cohort of animals or humans, which has undergone bariatric surgery and mechanistic studies evaluating bodily fluid or tissue samples are nonexistent or of secondary endpoints. Application that focuses entirely on in vitro investigations. Epidemiologic investigations as the primary focus of the application. Animal or human studies that do not evaluate tissue and/or bodily fluid samples collected from participants who have undergone bariatric surgery, some of which developed cancer after surgery. Application, which includes a clinical trial that does not have a bariatric surgeon as a key investigator on the team. NOTE: Applicants to this FOA are strongly encouraged to contact NCI staff as soon as possible in the development of the application (preferably no later than 12 weeks prior to the application due date) to discuss the details of their proposed clinical trial, so that NCI staff can help the applicant understand whether the proposed clinical trial is within the goals and mission of the NCI and is appropriate for this FOA.