Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this funding opportunity announcement is to request applications that propose mechanistic investigations of the links between diet, lipid metabolism and tumor growth and progression. It is anticipated that this program will support fundamental studies designed to identify and define the molecular mechanisms through which lipid metabolism mediates tumor growth and progression, focusing specifically on the central role lipids play in linking diet with the biology of cancer; bridge the historically divided fields of nutrition and molecular metabolism; and stimulate research and tool development in this emerging area, which faces particular challenges because of the complexity of lipid biochemistry. For this announcement, unpublished preliminary data are limited to one figure, comprising no more than one-half page, to facilitate the entry of qualified new investigators to the field.

Background

Cancer cells alter the regulation of their metabolic machinery, both to meet their increased biosynthetic and bioenergetic needs and to defend against the increased levels of free radicals generated by the upregulation of oxidative metabolism. The nutrients required to support an active metabolism can be imported directly from blood plasma or tumor interstitial fluid; they can also be acquired by parasitizing the surrounding tumor microenvironment. Recent work has documented the contributions of both neighboring stromal cells, such as cancer associated adipocytes (CAAs) and cancer associated fibroblasts (CAFs), and the surrounding extracellular matrix to tumor metabolism. An equally important but less well appreciated source of fuel and biosynthetic building blocks is diet, which has been shown to impact the availability of various macronutrients in the tumor microenvironment both directly and indirectly.

Although the association between diet and cancer risk is well established, the influence of diet on tumor growth and progression is less understood. This is due partly to the challenges of defining and controlling dietary variables in patient populations, and partly to the complexity of the tumor microenvironment, which may buffer subtle changes in the concentration of some metabolites. Different dietary patterns may also have different effects depending on the tissue from which the tumor originates. For example, a high fat diet has been linked to worse outcomes for breast, colorectal, and prostate cancer patients. In support of this epidemiological evidence, studies in mouse models have found that a high fat diet significantly alters the levels of a subset of serum metabolites, and may promote tumor growth and angiogenesis even in the absence of weight gain. In contrast, a lower carbohydrate diet with a higher fat content, particularly plant-based fats, is associated with longer survival times in some prospective studies of pancreatic cancer patients.

Recent work has suggested that lipid metabolism plays a central role in connecting diet and tumor growth and progression, both by promoting cellular proliferation and by regulating anti-tumor immunity. Lipids are a structurally diverse class of macromolecule that play a variety of biological roles; they can act as signaling molecules, be oxidized to provide energy in the form of ATP, or serve as the physical building blocks of cellular membranes. Lipid metabolism is highly plastic, and is commonly deregulated in cancer cells. Multiple different dietary perturbations have now been reported to directly influence lipid metabolism in tumors. For example, in mouse models of pancreatic ductal adenocarcinoma or non-small cell lung carcinoma, caloric restriction impairs the activity of stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the rate-limiting step in the synthesis of monounsaturated fatty acids, in tumor cells; the resulting imbalance in saturated and unsaturated fatty acids impairs tumor growth. Although a ketogenic diet also inhibits SCD activity in these mouse models, it supports tumor growth by increasing lipid availability and thus maintaining a balanced ratio of saturated and unsaturated fatty acids. A ketogenic diet has also been reported to raise the levels of NADH in a murine pancreatic cancer model, resulting in a sensitization of tumors to conventional cytotoxic chemotherapy. Dietary restriction of serine and glycine has been found to produce an accumulation of toxic deoxysphingolipid species that limits tumor growth in xenograft mouse models of colon cancer; sphingolipids are canonically derived from serine, which is synthesized from glycine, highlighting the need for an improved understanding of the connections between the biosynthesis of lipids and other macromolecules in cancer.

Diet has also been shown to influence tumor growth and progression through lipid-mediated effects on cells in the tumor microenvironment. In mouse models of oral squamous cell carcinoma or melanoma, short term exposure to dietary palmitic acid, a saturated fat found in meat, dairy, palm and coconut oil, induces changes in gene expression that stimulate metastasis by promoting regeneration of tumor-activated Schwann cells. A diet high in linoleic acid, a polyunsaturated fat found in vegetable oils, nuts, seeds, meat, and eggs, has also been reported to promote tumor progression in an immunocompetent mouse model of breast cancer by inducing mitochondrial dysfunction in T cells; oleic acid, which is a monounsaturated fat, did not have the same effect. The transcription factor SREBP, which is itself regulated by intracellular cholesterol levels, has been shown to promote the function and specialization of regulatory T cells by controlling multiple steps in lipid metabolism, but a detailed description of how diet-driven variations in the level and/or composition of lipids in serum or tumor interstitial fluid influence immune cell function is lacking.

Finally, diet-sensitive interactions between the tumor and the tumor microenvironment can influence tumor growth and progression in two independent but non-mutually exclusive ways. First, tumor metabolism may respond to diet-derived metabolites in a way that creates a permissive tumor microenvironment. For example, in a mouse model of colon cancer, a high fat diet causes opposing metabolic changes in tumor and CD8+ T cells; while tumor cells increase fat uptake in response to the higher levels of circulating lipids introduced by a high fat diet, CD8+T cells do not. This results in a local depletion of essential metabolites from the tumor microenvironment. Overexpressing the prolyl hydroxylase PHD3 in tumor cells reduces fatty acid uptake, increases palmitate availability in tumor interstitial fluid, and reduces tumor growth as a result of improved T cell function. Second, diet may shape the surrounding stromal environment to be pro-tumorigenic. Overnutrition leads to increased production of the adipokine chemerin, which regulates adipogenesis and adipocyte metabolism; chemerin is also overexpressed in clear cell renal carcinomas, where it maintains high levels of the transcription factor HIF2a and promotes tumor progression by suppressing fatty acid oxidation. The role chemerin plays in the progression of other cancers is not well studied, but it has been reported to directly stimulate cancer cell growth, proliferation, migration, and invasion in multiple tumor types, as well as to recruit tumor-supporting stromal cells, stimulate angiogenesis, and promote tumor suppression through immune-mediated effects.

Specific Objectives for this FOA

This FOA, which aligns with Goal 4 of the recent NIH Strategic Plan for Nutrition Research, will provide support for mechanistic investigations of the links between diet, lipid metabolism and tumor growth and progression. Studies that investigate high-fat, ketogenic diets are of particular interest, since the limited data that are currently available indicate they can produce highly dichotomous effects on tumor progression, depending on tumor type and the presence or absence of specific driver mutations. Mechanistic studies of dietary manipulations that perturb cancer cell metabolism in the absence of weight gain or overnutrition are also of particular interest. Addressing these and other relevant problems will improve our understanding of the biology that drives tumor growth and progression, and may inform the future development of novel therapeutic approaches. However it should be noted that for this FOA, plans for clinical translation are not required, although applications may have aims that illustrate translational potential.

Examples of responsive research questions include, but are not limited to:

• How do known driver mutations such as p53, KRAS, and MYC influence lipid metabolism in tumor cells in response to diet?
• What are the molecular mechanisms that moderate the differential effects of different biochemical species of dietary lipids, such as palmitate and linoleic acid, on tumor progression?
• How do diet-driven variations in the level and/or composition of fatty acids in serum or tumor interstitial fluid impact any or all of the following molecular processes in tumor and stromal cells?

• lipid-mediated signaling
• de novo lipogenesis
• mitochondrial function
• the production of reactive oxygen species

• How are alterations in diet-responsive lipid metabolism in tumors buffered or enhanced by the tumor microenvironment?
• What are the molecular mechanisms through which diet-responsive circulating factors such as adipokines and steroid hormones influence cancer cell metabolism and tumor progression?
• How does dietary composition affect lipid metabolism in tumors and the tumor microenvironment in the absence of weight gain?

Applications that examine how any of the above topics contribute to health disparities are welcome and encouraged.

To ensure appropriate expertise in nutrition, all applicants are encouraged to include a co-Investigator or use an MPI structure as appropriate to the work proposed.

Awardees will be expected to collaborate, share data and expertise, and participate in joint activities, including any NCI-organized working group(s) drawn from all funded U01 and UH2 research projects as are jointly determined to be needed by the awardees and participating NCI staff. Other NCI awardees with relevant expertise may be invited to join the working group(s) as associate members.

Recipients of awards under this FOA will also be expected to present their results at a virtual annual meeting that will be open to the scientific community at large.

Non-responsive Applications

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:

Applications that do not propose fundamental, mechanistic investigations, and/or that fail to include appropriate expertise in nutrition, will also be considered non-responsive.

To facilitate the entry of qualified new investigators, especially new clinical investigators, into the field, preliminary data will be limited; applications including unpublished data more than one-half page or more than one figure will be considered noncompliant with the FOA instructions and will not go forward to review. Applicants with substantial preliminary data are encouraged to apply to the related U01-based funding opportunity.

Applicants are strongly encouraged to contact the program staff listed in Section VII of the announcement regarding the responsiveness of their project.

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM)– Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Kristine Willis, Ph.D.
Telephone: 301-792-1338
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

In addition, due to its transdisciplinary nature and the focus on collaboration and expertise sharing, this FOA strongly encourages the appropriate use of diverse scientific environments and resources to support this type of integrative approach to cancer research. It is recognized that there may be instances where a single institution or performance site will already have the combined capability and resources to support a nutrition science perspective to study an important problem in cancer research and may not need additional performance sites.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

In addition, due to its transdisciplinary nature and focus on collaboration and expertise sharing, this FOA strongly encourages either the inclusion of significant co-Investigators and/or the use of the multi-PD/PI option. This FOA is open to all collaborating teams with formal training and expertise in both nutrition sciences and cancer research. Formal training and expertise can be established through undergraduate or graduate degrees or through a body of work that demonstrates contribution to the field. It is recognized that there may be instances where a single PD/PI will already have the combined expertise to bring a nutrition science perspective to study an important problem in cancer research and may not need to use the multi-PD/PI option.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Biosketch: Ensure that expertise in nutrition is appropriately reflected in at least one biosketch.

Research Strategy: Applicants are instructed to structure the Research Strategy using the standard sub-sections of Significance, Innovation, and Approach as defined in the SF424 instructions. Under these sub-sections and in addition to the standard content, applicants are required to address the following mandatory elements:

Significance:

• Clearly describe how the proposed studies link dietary variables to tumor growth and/or progression.

• Describe how one or more of the dietary variables to be studied are proposed to have a causal effect on lipid metabolism-mediated tumor growth and progression.

Innovation:

• Describe how the proposed experiments will generate data that substantiates a previously unknown connection between diet and lipid metabolism within the tumor itself or between diet and some cell non-autonomous factor, such as systemically circulating molecules or non-cancerous cells in the tumor microenvironment, that influences tumor growth and progression by acting on lipid metabolism. 

Approach:

• Provide clear details of the composition of any and all diets that will be used in proposed experiments. For example, there are several ways to formulate a high fat or high calorie diet; the content of the diet should be defined as precisely as possible.

• Clearly explain how the proposed approach will identify, or will further our understanding of, the cellular and/or molecular mechanisms through which diet influences some aspect of lipid metabolism to causally influence tumor growth and/or progression.

• Wherever applicable, describe how proposed models will provide a window into the effects of systemic, stromal, and/or microenvironmental factors on tumor metabolism.

• Though preliminary data (including findings to support proposed approaches) are not required, if limited preliminary data are provided, they will be evaluated. In lieu of preliminary data, applicants may provide the underlying logic or rationale for pursuing the project in the manner proposed. Summarize what are believed to be the major challenges and described alternative approaches that may need to be pursued. 

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by the NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

For this particular announcement, note the following:

The priority for this FOA is to stimulate fundamental cancer research that will address knowledge gaps and current technical challenges that limit our understanding of the connection between (1) diet and nutrition and (2) the cancer-relevant catabolism and anabolism of lipids, including the roles these metabolic processes play in supporting the function of lipids as energy sources, signaling molecules, post-translational modifications, and/or components of physical structures such as membranes. Since lipids are both the building blocks and end products of other metabolic reactions, applications may involve studies of the biosynthesis or degradation of other macromolecules as they specifically relate to lipid metabolism.

Applications are not limited to those that propose modifications of dietary lipids. Any dietary manipulation that has a downstream effect on some aspect of lipid metabolism in tumors, or on some tumor cell non-autonomous factor, such as systemically circulating molecules or non-cancerous cells in the tumor microenvironment, that influences tumor growth and progression by acting on lipid metabolism, is of equal interest.

Applications do not need to show any potential for direct clinical translation. Potential for clinical translation is not a requirement for this FOA.

The UH2 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. A UH2 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Note for this FOA, however, that unpublished preliminary data are limited to one figure, comprising no more than one-half page.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

For this FOA: How likely are the proposed studies to link dietary variables to tumor growth and/or progression? How likely is the proposed work to open new avenues of inquiry into the effects of one or more dietary variables on lipid metabolism-mediated tumor growth and progression?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance, and organizational structure appropriate for the project?

For this FOA: How suitable is the expertise of the investigative team in the areas of nutrition and the analysis of dietary variables?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

For this FOA: How likely is the proposed research to generate data that substantiates a connection that might reasonably be inferred based on existing literature, but that has not yet been formally demonstrated between diet and lipid metabolism within the tumor itself or between diet and some cell non-autonomous factor, such as systemically circulating molecules or non-cancerous cells in the tumor microenvironment, that influences tumor growth and progression by acting on lipid metabolism?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

For this FOA: How likely is the proposed approach to identify, or to further our understanding of, the cellular and/or molecular mechanisms through which diet influences some aspect of lipid metabolism to causally influence tumor growth and/or progression? Where the research plan incorporate one or more models, how well do those models provide a window into the effects of systemic, stromal, and/or microenvironmental factors on tumor metabolism?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment, and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Cancer Advisory Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.
• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH's purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility: 

• Overseeing the scientific progress of the Research Project, analyzing and interpreting research data, reporting results to the scientific community, and disseminating approaches, methods, models, software, and tools broadly;
• Agreeing to be an active participant in group activities organized for recipients by NCI staff, including attending the virtual Annual Investigators Meeting and other relevant NCI-sponsored meetings and workshops;
• Collaborating with other NCI recipients to advance research on the connections between diet, lipid metabolism, and tumor growth and progression;

• Abiding by all directives issued by NCI program officials responsible for supervision of the awarded project, consistent with the applicable rules and regulations governing cooperative agreements;
• Reporting progress to the NCI program officials on all research and activities annually. The PD(s)/PI(s) may be expected to provide additional information, outside the scope of the standard reporting requirement, as needed and requested by program staff members on a semi-annual basis;
• Providing other information as might be requested by project scientist (e.g., on project milestones, methodology, procedures, etc.)
• Ensuring that data are deposited in a timely manner in appropriate publicly available databases and that models, software, and other tools and resources developed as part of this Research Project are made publicly available according to NIH and NCI policies;
• Ensuring that results of the Research Projects are published in a timely manner;

• Participating in the NCI-coordinated evaluation of awards made under this FOA;
• Facilitating collaboration and validation of experimental concepts and observations on the topic of diet, lipid metabolism, and tumor growth/progression by participating in any scientific working group(s) jointly determined to be needed by the recipients and participating NCI staff; and
• Notifying NCI program staff members about research pilot projects.

Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to the recipient if the investigators are unable to meet the performance requirements set forth in the required policies and procedures.

NCI program staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards. The substantially involved NCI program staff member(s), acting as project scientist(s), will coordinate in a centralized fashion various activities of the recipients. Specific responsibilities of the NCI project scientist(s) will include, but will not be limited to the following:

• Monitoring the specific technical direction of projects, including recommending approval of changes in experimental approaches;
• Assisting both individual award recipients as well as any scientific working group(s) jointly determined to be needed by the recipients and participating NCI staff in avoiding unwarranted duplications of effort;
• Facilitating collaborative research efforts between recipients;
• Serving as a resource for recipients, particularly in making them aware of other ongoing NCI activities that may be relevant to the study of diet, lipid metabolism, and tumor growth and progression;
• Assisting the recipients as a resource by facilitating their broader interactions with other NCI and NIH programs to disseminate results, tools, and models and take advantage of existing NIH/NCI resources and infrastructures;
• Evaluating the effectiveness of standards and best practices developed by recipients to link dietary and metabolic research, and promoting the adoption of these standards and best practices by the broader community, including through publications;
• Monitoring the operations of award recipients and making recommendations on overall project directions;
• Reviewing the progress of the program;
• Leading the organization of annual meetings, specialized workshops, and webinars of the consortium, including meetings of any working group(s) jointly determined to be needed by the recipients and participating NCI staff.

The substantially involved NCI staff members will not attend peer review meetings. If such participation is deemed essential, these individuals will seek NCI waivers according to the NCI procedures for management of conflict of interest. In addition, an NCI program director acting as a program official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. 

Areas of Joint Responsibility include: 

Since the purpose of this FOA is to establish and/or further develop collaborative arrangements between extramural investigators, including but not limited to the identification of new research directions and models, many responsibilities are shared between recipients and NIH staff and will require close coordination. Responsibilities will be divided between recipients and NIH staff, as described above.

Dispute Resolution: 

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a representative chosen by two-thirds vote of recipients without input from NIH staff, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. 

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

For applications that emphasize tumor cell autonomous mechanisms:

Kristine Willis, Ph.D.
National Cancer Institute
Telephone: 301-792-1338
Email: [email protected]

For applications that emphasize tumor cell non-autonomous mechanisms:

Natalia Mercer, Ph.D.
National Cancer Institute
Telephone: 240-276-6220
Email: [email protected]

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: [email protected]

Amy Bartosch
National Cancer Institute (NCI)
Telephone: (240) 276-6375
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.