NIH – Metabolic Dysregulation and Cancer Risk Program, Research Grants: a Transdisciplinary Approach to Obesity-Associated Research (U01 Clinical Trial Optional)

July 23, 2021 by


The National Cancer Institute (NCI) invites research grant applicationsfor transdisciplinary studies that will enhance our knowledge of the dynamics and underlying mechanisms that link obesity, metabolic dysregulation and increased cancer risk as part of the Metabolic Dysregulation and Cancer Risk Program. Through this Funding Opportunity Announcement (FOA), the Metabolic Dysregulation and Cancer Risk Program will focus on metabolic dysregulation as the key process linking obesity with cancer risk.

For the purpose of this FOA, metabolic dysregulation is defined as alterations in glucose utilization and storage, insulin sensitivity, and/or lipid metabolism. Applications should specifically seek to advance our understanding of how metabolic dysregulation in individuals affects cancer risk and identify mechanisms that will enhance (i) cancer risk prediction, (ii) screening for high-risk individuals in clinical settings, and (iii) identification of potential targets for preventive and therapeutic interventions.

This FOA is published in parallel with RFA-CA-21-022 “Coordinating Center for the Metabolic Dysregulation and Cancer Risk Program: a Transdisciplinary Approach to Obesity-associated Research (U24 Clinical Trial Not Allowed)”. The individual research grants and the Coordinating Center funded under these FOAs together will constitute the Metabolic Dysregulation and Cancer Risk Program.


Obesity as a public health concern

Obesity (i.e., a state of chronic positive energy balance) is an established risk factor for multiple cancers, and emerging data links obesity to the early onset of several types of cancer. The obesity-cancer link is a pressing concern due to the escalating prevalence of obesity, especially in Western populations. In addition, the burden of obesity-associated cancer is unequal, as it afflicts certain communities in the United States, specifically racial/ethnic minority populations at greater rates than the overall population.

Obesity and metabolic dysregulation

Epidemiologic findings indicate that cancer risk may be lower among metabolically healthy overweight/obese individuals compared to overweight/obese individuals with metabolic dysfunction. Thus, it has been hypothesized that cancer susceptibility associated with obesity may be due to sustained metabolic dysregulation, rather than the adiposity per se. Both preclinical and clinical studies indicate that hypoglycemia reduces tumor incidence. For example, in animal models prolonged reduction in daily caloric intake or daily intermittent fasting (to reduce glucose availability) has been shown to reduce cancer incidence. In clinical studies, intermittent fasting (IF) decreases insulin resistance, lowers levels of IGF-1, leptin, and glucose, and increases adiponectin, all of which are linked to a decreased risk of several malignancies. Weight-loss interventions such as bariatric surgery in severely obese individuals have also been shown to lower risk of several obesity-associated cancers (e.g., postmenopausal breast cancer, endometrial cancer, colon cancer) and to influence their metabolic health (e.g., decrease insulin resistance).

Obesity creates a chronic disease-susceptible state

Obesity can be conceptually viewed as a “disease-susceptible state” and/or a “metabolically dysregulated state.” This state of disease predisposition can progress to several chronic pathologies, including cancer. Chronic disease states in which obesity is a known contributor (e.g. type 2 diabetes mellitus, non-alcoholic fatty liver disease [NAFLD], and metabolic syndrome) share biomarker profiles (insulin resistance, hyperinsulinemia, inflammation, hyperglycemia, and dyslipidemia) that reflect metabolic dysregulation, and that plausibly contribute to the initiation and development of obesity-associated cancers through unknown mechanisms.

Gaps in knowledge

Obesity-associated etiologic pathways are likely to be heterogeneous and to vary by severity and duration of obesity, cancer type, and by the metabolic dysregulation specific to the individual. Studies of endogenous and exogeneous factors with discrete impact on obesity, metabolic functions, and cancer risk are needed to understand the molecular interactions between obesity-associated metabolic dysregulation and critical biologic pathways (e.g., inflammation, sex hormones, adipokines) that impact cancer risk. These factors include, but are not limited to, local and systemic immunomodulatory effects of the gut microbiota, sleep cycle, and environmental exposures (phthalates, dietary metabolites). How these factors influence the obesity-metabolism-cancer relationship remains poorly understood and offers an opportunity to identify novel targets for new prevention and treatment strategies.

To address the lack of data and specimens from human studies of obesity-induced metabolic dysregulation and cancer risk, and increase the clinical relevance of pre-clinical models (e.g. animal or computational models), applicants should propose approaches that use observational or interventional human studies and, when feasible, include well-powered representation of racial/ethnic minorities and understudied populations to sufficiently address the unequal burden of obesity-associated cancer in those populations.

Key Dates:

Open Date (Earliest Submission Date): September 06, 2021
Letter of Intent Due Date(s): September 1, 2021
Applications Due: October 6, 2021

URL for more information:

Filed Under: Funding Opportunities