Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Cancer Institute (NCI)
Funding Opportunity Title	The Role of Microbial Metabolites in Cancer Prevention and Etiology (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	Reissue of PAR-11-152
Related Notices	June 3, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications. May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.
Funding Opportunity Announcement (FOA) Number	PAR-13-159
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.393, 93.396
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) encourages preclinical and clinical research that will describe the effect of microbially generated metabolites in cancer prevention/ progression and the molecular mechanisms underlying these effects: proliferative/apoptotic responses, cytokine production, inflammatory and immunomodulatory effects locally and/or distant. This FOA encourages pre-clinical and clinical studies that will describe the variability in the bacterial metabolites production and their contribution to cancer prevention/promotion among various racial and ethnic groups. Due to inconsistent responses to dietary interventions, this research is necessary to identify who might benefit from specific dietary recommend ations and who might be placed at risk. It is important to identify the factors that contribute to differences in response to foods and food components and to identify early markers that will identify those who will receive maximum benefits from dietary change. As these are complex questions this program will facilitate interdisciplinary collaborations among scientists engaged in research in cancer prevention and microbiology, nutrition, cancer cell biology, and cancer disparities. To achieve this goal all applications are encouraged to include multiple Program Director(s)/Principal Investigator(s) with expertise in cancer biology, microbiology, nutrition, analytical chemistry or genetics. Investigations may use either clinical or preclinical approaches. All awardees are expected to attend an annual meeting with NIH personnel to report new findings and coordinate the exchange of new information and methodologies with interested colleagues and to promote collaboration.

Posted Date	April 4, 2013
Open Date (Earliest Submission Date)	October 14, 2013
Letter of Intent Due Date(s)	October 14, 2013; October 14, 2014
Application Due Date(s)	November 14, 2013, November 14, 2014, 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.
AIDS Application Due Date(s)	November 14, 2013, November 14, 2014, by 5:00 PM local time of applicant organization.
Scientific Merit Review	March 2014; March 2015
Advisory Council Review	May 2014; May 2015
Earliest Start Date	July 2014; July 2015
Expiration Date	November 15, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the 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 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this FOA is to stimulate preclinical and clinical research that will describe the effect of microbially generated metabolites in cancer prevention/progression and the molecular mechanisms underlying these effects: proliferative/apoptotic responses, cytokine production, inflammatory and immunomodulatory effects locally and/or distant. This FOA encourages clinical studies that will describe the variability in bacterial metabolite production and their contribution to cancer prevention/promotion among various racial and ethnic groups. Due to inconsistent responses to dietary interventions, this research is necessary to identify who might benefit from specific dietary recommendations and who might be placed at risk. It is important to identify the factors that contribute to differences in response to foods and food components and to identify early markers that will identify those who will receive maximum benefits from dietary change. As these are complex questions this program will facilitate interdisciplinary collaborations among scientists engaged in research in cancer prevention and microbiology, nutrition, cancer cell biology, cancer disparities. To achieve this goal all applications are encouraged to include multiple Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) with expertise in cancer biology, microbiology, nutrition, analytical chemistry or genetics. Investigations may use either clinical or preclinical approaches. All awardees are required to attend an annual meeting with NIH personnel to report new findings and coordinate the exchange of new information and methodologies with interested colleagues and to promote collaboration.

The balance between beneficial and detrimental bacteria can be influenced by dietary compounds which can preferentially influence the growth of one or more strains. It seems more and more likely that bioactive food components play a dual role by promoting the substrate for metabolites with anticancer properties and facilitating the production of these metabolites by promoting the growth of probiotics. Inulin, a fermentable carbohydrate, has been found to stimulate growth of lactobacilli and bifidobacteria in human. Providing wild blueberry powder drink to healthy humans for 6 weeks increased potentially beneficial bifidobacteria. A pomegranate by-product oligomer composed of gallic acid, ellagic acid and glucose units appears to increase Bifidobacterium and Lactobacillus in humans. Other preparations such as grape pomace polyphenols have been found to stimulate Lactobacillus acidophilus growth in vitro but their influence in vivo and the amounts needed remain to be discovered. More information is needed to evaluate the temporal response to food and food components as modifiers of specific microbial growth and its relationship to the entire microbiome.

Several dietary components are known to be metabolized by intestinal bacteria and some of these appear to have cancer protective characteristics. A few of these studies are briefly discussed below as examples, but there are still many unanswered questions regarding these metabolites and other microbial metabolites.

1. Equol and O-desmethylangolensin (DMA) are microbially produced metabolites from daidzein, an isoflavonoid found in soy. Equol has been found to inhibit the growth of benign and malignant prostate epithelial cells in vitro at concentrations that can be obtained naturally through dietary soy consumption. The specific bacterium/bacteria responsible for equol and O-DMA production in humans have yet to be definitively identified. However, in vitro and animal studies have suggested that equol and O-DMA are more biologically active than their precursor daidzein and may offer protections against some cancer, i.e. prostate and breast. Asians are more likely to produce this metabolite than Caucasians and it may account for differential risk across populations. As an example, mammographic density has been reported to be about 39% lower in equol producers compared with non-producers.

2. Lignans are biphenolic compounds that naturally occur in foods of plant origin such as whole grains, seeds, fruits and vegetables, and beverages, such as coffee and tea. Plant lignans are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone and a substantial reduction in colorectal adenoma risk was observed among subjects from a case- control study with high plasma concentrations of enterolignans, in particular, enterodiol. Treatment with enterolactone and enterodiol, two lignan metabolites, alone or in combination, inhibited SW480 cell growth in a dose- and time-dependent manner through cytostatic and apoptotic mechanisms. Enterolactone also suppresses colo 201 human colon cancer cell growth in vivo in athymic mice. Not all lignans are effective since matairesinol and secoisolariciresinol feeding to Min mice did not inhibit intestinal tumorigenesis. However, secoisolariciresinol diglycoside from wheat bran was protective in Min mice. The reasons for these speciation differences deserve further examination. An individual’s genotype may influence the response to lignans. Women homozygous for the A2 allele of cytochrome P450c17 appear to benefit more from higher plasma enterolactone concentrations and a high consumption of dietary precursors than women without this allele. This also suggests that an individual’s genetic background, their dietary patterns and their microbiota interact and must be considered simultaneously for cancer prevention. A better understanding about how genetic polymorphisms influence the biological response to bacterial metabolites of bioactive food components is warranted.

3. Ellagic acid is a polyphenol present in many foods including strawberries, raspberries, walnuts and pomegranates. It has been reported that ellagic acid possess a plethora of biological properties including antioxidant and cancer protective activities. Its intake has been implicated in colon and prostate cancer risk reduction. Ellagic acid is metabolized by human colonic microflora to yield urolithins A and B. UROA (urolithin-A pomegranate microbiota-derived metabolite) is an active anti-inflammatory compound derived from pomegranate ingestion in healthy subjects, whereas in colon inflammation, the effects could be due to the non-metabolized ellagitannin-related fraction. Both PE (spell out these and following abbreviations) and UROA decreased inflammation markers (iNOS, cycloxygenase-2, PTGES and PGE 2 in colonic mucosa) and modulated favorably the gut microbiota. Similar to equol, the production of urolithins has been hypothesized to depend on the composition of the microflora of each individual because there is large inter-individual variability in production. This variability was demonstrated in a human supplementation study: when 10 volunteers consumed 25 g fresh strawberries, excretion of urolithin B derivatives ranged from 0.05 to 6.3%; when they consumed 35 g of walnuts, excretion ranged from 1.2 to 81%; and when they consumed 300 ml of oak-aged red wine, excretion ranged from 1.8 to 7.4%. Thus, the potential biological effects for this cancer protective dietary compound may also be different among individuals depending on their microflora. It is not known whether genetic polymorphisms in ellagic acid metabolizing enzymes (i.e. catechol-O-methyltransferase and glucuronyl transferases) might be associated with differences in ellagic acid metabolism, urolithin production and ultimately cancer risk.

4. Polyphenols and in particular higher-molecular-weight polyphenols including proanthocyanidins or oxidized polymeric polyphenols are poorly absorbed and thus become substrates for microbes. These polyphenols are abundant in wine, tea, chocolate and many fruits. Ferulic acid, which is present in considerable quantities in most fruits, vegetables and cereals, forms three major metabolites when incubated with human microbiota. These metabolites have also been found in human fecal samples and are more potent inhibitors of prostaglandin metabolism than the parent compound in vitro. The physiological significance of these microbial metabolites and whether this inhibition of inflammatory pathways contributes to a decreased cancer risk when consuming a polyphenol rich diet remains to be determined.

5. Butyrate, a short-chain fatty acid produced by colonic bacterial fermentation is able to induce cell growth inhibition and differentiation in colon cancer cells at least partially through its capacity to inhibit histone deacetylases. Despite a long-suspected role in the development of human colorectal cancer (CRC), the composition of gut microbiota in CRC patients has not been adequately described. Reduction of butyrate producers and increase of opportunistic pathogens may result from a major structural imbalance of gut microbiota in CRC patients.

Host Interactions with Microbiome: Host interactions with the microbiome are both local, in the gastrointestinal tract lumen, or distant, involving hormonal intermediates, microbial metabolites, and immunological messengers. The gut microbiota, which is considered a causal factor in many metabolic diseases, as shown best in animals, is under the dual influence of the host genome and nutrient (bioactive food component) supply. Microbially generated metabolites may influence a number of cellular processes which can influence health and/or disease risk. Perturbations in the processes may influence the relative importance of microbes in reducing or accentuating cancer risk.

Inflammation is recognized as factor in the development of several cancers. Modulation of intestinal microbiota by non-digestible carbohydrates may serve as a strategy to reduce inflammation in inflammatory bowel disease (IBD). Colitis has been found to be significantly reduced when fructooligosaccharides are given in model systems. This change appeared to relate to an increase in the abundance of Bifidobacterium and reduction in Clostridium cluster XI and C. difficile toxin gene expression. It is increasingly accepted that probiotics contribute in a positive way to gut homeostasis possibly by influencing inflammatory processes.

Cellular energetics and obesity are also linked to increased cancer risk. Investigators have used genetic sequencing to determine that obese individuals had more Firmicutes and nearly 90% less Bacteroidetes than lean individuals. When obese volunteers consumed a low-fat or low-carbohydrate diet and lost about 25% of their body weight, the proportion of Firmicutes in their colon dropped and that of the Bacteroidetes rose. Similar to humans, mice that are genetically obese (ob/ob) have a higher proportion of intestinal Firmicutes and 50% fewer Bacteroidetes than their lean siblings. When germ-free mice were colonized with either the microbiota from obese (ob/ob) or lean (+/+) littermates, the mice given the microbiota from obese mice extracted more calories from their food and had a significantly greater increase in total body fat than in mice colonized with the microbiota from lean mice. These data suggest that differences in the efficiency of caloric extraction from food may be determined by the composition of the microbiota, which in turn, may contribute to differences in body weight. Although there is ample evidence for a role of gut microbiota in the development of obesity in rodents the magnitude of its contribution to human obesity remains to be clarified.

Specific research areas of interest include, but are not limited to, the following areas:

• Mechanisms by which microbially generated flaxseed metabolites are influenced by genetic differences in xenobiotic enzymes.
• Mechanisms by which microbially generated soy metabolites may influence the activity of human estrobolome.
• Identify and evaluate differences in the biological effects of microbially generated metabolites that may contribute to cancer health disparities among various racial ethnic and socioeconomic populations.
• Identify and describe functional changes in the microbiome following meat consumption with or without modified starches on nitro compound formation and metabolism.
• The role of black tea polyphenol metabolites generated by gut bacteria on inflammation and colorectal cancer risk reduction.
• The interrelationship between ellagic acid metabolism and NFkB polymorphisms.
• Evaluate interferon delivery as a mechanism by which inulin and associated beneficial bacteria growth changes might reduce inflammation.
• Evaluate the role of dietary animal fat on the population of sulfur-reducing bacteria and their production of genotoxic metabolic products such as hydrogen sulfide (change in number of microorganism or enzyme activity).
• Identify and characterize microbial metabolites that are caused by ginseng and which influence microbial homeostasis and dysbiosis using metabolomics technologies.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect the actual needs of the proposed project.
Award Project Period	The total project period may not exceed 5 years.

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

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)

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)
• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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 underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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.

Applicants are encouraged to consider designating multiple PD(s)/PI(s) with different areas of expertise such as, but not limited to, microbiology, nutrition, cancer biology, analytical chemistry, or genetics. Multiple PD(s)/PI(s) option may thus be used to address one of the goals of this initiative, which is to facilitate interdisciplinary collaborations among scientists engaged in nutrition, cancer prevention, cancer cell biology research, and cancer disparities research with those conducting studies with gut microorganisms.

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Gabriela Riscuta, M.D., CNS
Nutritional Science Research Group
Division of Cancer Prevention
National Cancer Institute
9609 Medical Center Drive, Room 5E568
Bethesda MD 20892-9788 (for regular mail)
Rockville, MD 20850 (for express delivery)
Telephone: 240-276-7118
E-mail: [email protected]

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

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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.

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.

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:

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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 DUNS number it provides on the application is the same number 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

In order to expedite review, applicants are requested to notify the NCI Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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).

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? 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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?

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

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?

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 six 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 six 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Cancer Institute, 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:

• 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.
• Will receive a written critique.

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 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.

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.

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

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 grantee’s business official.

Awardees 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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• Defining objectives and approaches, and to plan, conduct, analyze and publish results, interpretations, and conclusions of studies conducted under this program.
• The PD(s)/PI(s) assumes(s) responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 in accordance with these terms and conditions of the award.

Specific PD/PI rights and responsibilities will include the following:

• The PD(s)/PI(s) for each U01 award will have the primary authority and responsibility for the project as a whole, including defining the research objectives, conducting specific studies, analysis and interpretation of research data, and preparation of publications;
• Representatives of each U01 award will be expected to work with the NCI Project Scientist on the coordination of research program activities
• These actions may involve (but will not be limited to) the participation in the appropriate meetings and/or working groups, and/or teleconferences as needed;
• A PD/PI of each U01 project and at least one additional PD/PI or senior/key personnel member will participate in the annual consortium meeting;
• In addition to providing standard annual progress reports (see Section VI.3. Reporting), each U01 awardee will be responsible for providing other relevant information to the NCI Project Scientist, and will coordinate and cooperate with NCI staff and other members of the Program; and
• Each U01 awardee 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 HHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

A designated NCI Program Director acting as a Project Scientist will have the following responsibilities:

• Coordinating and facilitating the interactions among the U01 awardees under this initiative;
• Serving as liaison between the research awardees and NCI staff members and investigators involved in the program, facilitating interactions and scientific integration between the U01 awardees;
• Promoting collaborative research efforts that involve interactions with other NIH-supported projects, programs, and centers and assisting with the coordination of these efforts;
• Participating in program meetings;
• Reviewing all major transitional changes that the awardees might propose (e.g., a change in partnering institution) and advising on their appropriateness prior to implementation to assure consistency with the goals of this FOA;
• Providing technical assistance and advice to the awardees as appropriate;
• Assisting in the interaction between the U01 research awardees and investigators at other institutions, as appropriate for the program;
• Assisting in avoiding unwarranted duplication of effort with other NIH efforts;
• Monitoring institutional commitments and resources to the awardees;
• Suggesting reprogramming efforts, including options to modify projects/programs when certain objectives of this FOA are not met;
• Recommending withholding of support, suspension, or termination of a U01 award for lack of progress and/or adherence to required policies/procedures; and
• Organizing and conducting regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the awardees.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. A Program Official may also have substantial programmatic involvement (as Project Scientist) and may be the same person as the Project Scientist. The substantially involved NCI staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waivers according to the NCI procedures for management of conflict of interest.

Areas of Joint Responsibility include:

The NCI Project Scientist and the PD(s)/PI(s) of the U01 awards funded under this FOA will be jointly responsible for the coordination of intra-program activities and the scientific integration of individual projects. These responsibilities include joint participation in the Steering Committee.

The Steering Committee will be composed of two representatives of each awardee (two PDs/PIs, or a PD/PI and a second key member) and the NCI Project Scientist. Each full member will have one vote.

The members of the Steering Committee will select a chairperson (who cannot be an NCI Program staff member).

The Steering Committee will be responsible for developing strategies to address issues common to all of the projects funded by this initiative. The Steering Committee will pay special attention to issues of data integration, management, analysis, and public release and may establish subcommittees as necessary.

Awardees under this FOA will be required to accept and implement policies approved by the Steering Committee to the extent consistent with the applicable grant regulations.

The NCI Program staff members and the Steering Committee will organize and an annual meeting of the awardees of this initiative.

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. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, 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 awardee. This special dispute resolution procedure does not alter the awardee'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

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Phone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

Gabriela Riscuta, M.D., CNS
National Cancer Institute
Telephone: 240-276-7118
E-mail: [email protected]

Phillip Daschner, Ph.D. 
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6227
E-mail: [email protected]

Rina Das, Ph.D. 
Center to Reduce Cancer Health Disparities
National Cancer Institute (NCI)
Telephone: 240-276-6184
E-mail: [email protected]

Referral Officer
Division of Extramural Activities
National Cancer Institute
Telephone: 240-276-6390
E-mail: [email protected]

Heather Weiss
Office of Grants Administration
National Cancer Institute
Telephone: 240-276-6318
E-mail: [email protected]

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 Parts 74 and 92.