Key Dates

Related Announcements

NOT-CA-22-114 -Notice of Change to add PA-20-195 in NOT-CA-21-121

PAR-19-133 - Academic Research Enhancement Award for Undergraduate-Focused Institutions (R15 - Clinical Trial Required)

PAR-19-134 - Research Enhancement Award Program (REAP) for Health Professional Schools and Graduate Schools (R15 Clinical Trial Not Allowed

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-188 - NIH Pathway to Independence Award (Parent K99/R00 - Independent Clinical Trial Not Allowed)

PAR-20-292 - NCI Clinical and Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional)

PAR-21-038 - Stephen I. Katz Early-Stage Investigator Research Project Grant (R01 Clinical Trial Not Allowed)

PAR-21-300 - NCI Mentored Clinical Scientist Research Career Development Award to Promote Diversity (K08 Independent Clinical Trial Not Allowed)

PAR-21-301 - NCI Transition Career Development Award to Promote Diversity (K22 Independent Clinical Trial Not Allowed)

NOT-CA-22-114 - Notice of Change to add PA-20-195 in NOT-CA-21-121

Issued by

National Cancer Institute (NCI)

Purpose

Purpose

This Notice of Special Interest (NOSI) seeks to support new and ongoing basic research that provides a deeper understanding of the biology and molecular mechanisms that determine the outcome of key diet/nutrient/cell interactions during early tumor development. Specifically, studies that examine the tumor preventive or tumor-promoting effects of dietary modulation of nutrient sensor signaling pathways during early tumor formation (initiation and malignant progression from early lesions) in preclinical cell, organoid, and animal models, with the goal of identifying and testing potential molecular intervention targets.

Background

Dietary factor interactions with host nutrient-sensing pathways may have direct effects on transforming cells (genetic, epigenetic, metabolic, cell cycling) or may signal through associated stroma and microbial cells via inflammatory cytokines, mitogens, oncometabolites, and hormones. Recent evidence has shown that variations in dietary patterns can alter the human metabolome and influence individual health and cancer risk. However, there is a knowledge gap regarding the mechanisms of how excess or depleted nutrient levels are sensed and how this information is conveyed at the cell and tissue level to maintain homeostasis. In addition, there are large interpersonal variations in response to dietary patterns and dietary interventions. For example, ketogenic diets (high fat, low carbohydrate) that increase production of ketone bodies such as beta-hydroxybutyrate have pleiotropic effects, depending on both cell-intrinsic (cell type; epigenetic status) and cell-extrinsic factors (inflammatory state; microbiome), ranging from increased Notch signaling and immunosuppression to mTOR and inflammasome inhibition. Moreover, current general dietary guidelines were developed from population-based data and do not capture the effects of interpersonal variation in nutrient metabolism or diet-related cancer risk. For example, animal-based high-fat diets significantly increase the levels of deoxycholic acid (DCA), a secondary bile acid produced by microbial dehydroxylation of bile that has been shown to promote liver cancer in mouse models, but it is unknown how nutrition affects production of DCA. Given the complex relationship between diet and metabolic states, and the multiple levels at which metabolism operates, further research is needed to understand how diet affects cell and tissue nutrient- sensing associated signaling pathways that are critical to tumor initiation and progression.

Several classes of nutrient sensors have been identified that detect intracellular and extracellular levels of diet-derived macronutrients (carbohydrate, protein, lipids) and micronutrients (xenobiotics, vitamins, amino acids, and sugars). These sensors regulate signaling pathways critical to cell fate decisions in developing tumors. Some of these nutrient sensors are well known and characterized (e.g., vitamin D receptor), while others are much less well studied, (e.g., RAGE, PI3K, MONDO factors, G-protein Coupled Receptors, sterol and carbohydrate-responsive element-binding proteins (SREBP and ChREBP), and others). Studies investigating how these nutrient sensors affect tumorigenesis may identify novel molecular targets for cancer- preventive nutritional strategies.

Research Objectives

This purpose of this NOSI is to stimulate investigations of nutrient sensor signaling mechanisms that promote or inhibit carcinogenesis (affecting either cancer etiology or prevention).

Development of nutritional strategies that could modulate cancer-relevant nutrient-sensing pathways will require a better understanding of; i) the interpersonal variation in nutrient metabolism and individual’s metabolic response to changes in diet/dietary patterns, ii) the cell and molecular factors that control host responses to a given dietary regimen and how these mechanisms may vary between tissues, iii) the identification of dietary components (or their metabolites) and their signaling pathways that affect gene regulation, cellular processes and cell fate decisions important for cancer etiology, prevention, and progression, and iv) how these components interact at the cellular, tissue, and systems levels.

Examples of Responsive Proposals Include:

1. Determine how diet affects cell nutrient-sensing signal pathways during early tumor formation (from pre-malignant to early lesions), including specific nutrient effects on signaling pathways in stromal and microbial cells that may support or suppress tumor formation or progression via production/inhibition of oncometabolites or inflammatory factors.

2. Examine how nutrient sensing regulates and maintains metabolic homeostasis in early lesions during tumor development.

3. Determine how diet regulates nutrient-sensing signals that affect host genetic, epigenetic, metagenomic, metabolic, and stem cell changes, that support or suppress tumor formation and/or progression.

4. Identify critical nutrient-sensor signaling factors that are produced or inhibited in response to dietary changes or certain dietary patterns and determine the molecular mechanisms by which they impact tumor formation and progression.

5. Determine whether the genetic, epigenetic, and physiological characteristics of individuals (such as their microbiome or history of exposure to drugs and chemical agents) can be used to identify critical host factor/nutrient interactions that impact tumor risk.

6. Examine how nutrient sensing pathways cross-talk and coordinate with other signaling pathways, such as those triggered by hormones and growth factors, to regulate cell and tissue homeostasis.

7. Determine what nutrient-sensing factors and pathways mediate outcomes of certain dietary patterns such as alcohol consumption or a high sugar diet to promote systemic or local inflammation and a pro-tumorigenic environment

Examples of projects NOT responsive to this FOA:

1. Correlative studies on discovery/development of nutrition-based risk biomarkers

2. Translational studies for dietary treatments or adjuvant interventions in established tumors

3. Effects of caloric restriction/fasting/timing of food intake or intermittent fasting or physical activity studies

Application and Submission Information

This notice applies to due dates on or after February 5, 2022, and subsequent receipt dates through September 8, 2024.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-CA-21-121 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

Scientific/Research Contact(s)

Phillip J. Daschner, MSc
National Cancer Institute (NCI)
Telephone: 240-276-6227
Email: [email protected]

Sharon Ross, PhD, MPH
National Cancer Institute (NCI)
Telephone: 240-276-7124
Email: [email protected]

Amit Kumar, PhD
National Cancer Institute (NCI)
Telephone: 240-276-7617
Email: [email protected]

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: [email protected]