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.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

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

Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - 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. Notice of Funding Opportunity Description

Purpose

Through this Notice of Funding Opportunity (NOFO), the National Cancer Institute (NCI) solicits applications for the RNA Modifications Driving Oncogenesis (RNAMoDO) Initiative. This NCI initiative aims to promote fundamental studies in the emerging area of RNA modifications that underlie the oncogenic process, focusing on the central role of RNA modifications in translational reprogramming of cancer cells. RNA modifications have been recognized to exert a substantial impact on gene expression and function and their de-regulation has been linked to the cancer phenotype. In particular, recent insights point to the crucial role of mRNA, tRNA, and rRNA modifications in translational reprogramming during tumor initiation, progression, and adaptation to therapy. However, the molecular mechanisms underlying this reshaping of the translatome caused by dynamic changes in RNA modifications, as well as the interplay between different RNA modifications within and/or across RNA molecules during translation, are not understood and represent the focus of this initiative. This new program will be composed of up to five U01 grants that will be supported by this NOFO and work collectively to achieve the objectives of this initiative. The initiative aims to bring together experts in RNA modifications, translational regulation, and cancer biology to address and elucidate how dysregulations in mRNA, tRNA, and rRNA modifications could reprogram the translation machinery to drive cancer formation and progression.

Background

1.1. RNA Modifications

Gene expression, the conversion from genotype to phenotype, is a highly regulated process that involves the concerted activity of DNA, RNA, and protein molecules. Several RNA species have an essential role (mRNA, rRNA, tRNA, snRNA), while others (lncRNA, circRNA, miRNA, snoRNA, piRNA, eRNA, carRNA) fulfill regulatory functions during transcription, co-or post-transcriptional processing, and translation. It has been recognized that RNA molecules can undergo epigenetic base modifications and that these modifications lead to alterations in the stability, folding, localization, subsequent processing, and translation of these RNAs. Overall, more than 100 types of modifications have been reported in human, among them the most widespread and best characterized are N⁶-adenosine methylation (m⁶A), adenosine to inosine (A-to-I) deamination, cytosine to uracil (C-to-U) deamination, pseudouridylation (ψ), N¹-adenosine methylation (m¹A), 5-cytosine methylation (m⁵C), N⁷-guanosine methylation (m⁷G), N⁴-cytidine acetylation (ac⁴C), and ribose 2’O-methylation (2’-O-Me).

The discovery of cellular RNA modifiers, which introduce (‘writers’), remove (‘erasers’), or recognize (‘readers’) specific RNA modifications revealed that these epigenetic marks are often dynamic in nature and subject to regulatory control. Recent mechanistic work underscores the importance of these modifications for the regulation of gene expression and other fundamental cellular processes, and aberrations and dysregulation in RNA modification levels have been linked to disease phenotypes, in particular cancer.

1.2. RNA Modifications in Cancer

There is increasing evidence that RNA molecules become hyper-, hypo-, or mis-modified in cancer, and that the over- or under-expression, mutation, deletion, or post-translational modification of RNA modifiers are linked to the cancer phenotype and can drive oncogenesis and tumor progression. For example, aberrant deposition, removal, or recognition of N⁶-methyladenosine (m⁶A), the most predominant type of mRNA modification in mammals, is associated with diverse human cancers. In acute myeloid leukemia (AML), dysregulation of m⁶A by aberrant expression of either the FTO demethylase (‘eraser’) or the METTL3 methyltransferase (‘writer’) can lead to differentiation blockage and leukemogenesis. In glioblastoma (GBM), overexpression of the ALKBH5 demethylase is associated with poor clinical outcome, due to destabilization of FOXM1 transcription factor mRNA after m6A removal by the demethylase. The levels of m⁶A in mRNAs of hepatocellular carcinoma tissues were found to be decreased due to the downregulation of the methylase complex, which was associated with metastasis and worse prognosis. The A-to-I RNA editing of both coding and non-coding RNAs constitutes another prevalent type of modification that has been linked to the cancer phenotype. Due to the potential for recoding of protein coding sequences in mRNA through A-to-I editing, aberrant editing can increase protein heterogeneity and the production of neoantigens. For several other types of RNA modifications, including pseudouridine, m⁵C, m¹A, ac⁴C, m⁷G, and 2’-O-Me, oncogenic or tumor suppressor functions have been ascribed to the molecular players involved in relation to mRNA, tRNA, or rRNA modifications. Those insights establish RNA modifications as potential diagnostic or prognostic markers, and the RNA modifiers as possible therapeutic targets in cancer. In 2022, the first RNA modifying enzyme inhibitor entered a clinical phase 1 trial for solid cancers.

1.3. Convergence of mRNA, rRNA, and tRNA Modifications at the Onco-Ribosome

Protein synthesis is one of the most energy consuming cellular processes that is tightly regulated, allowing cells to adapt quickly to limited resources and cellular stress. Translational reprogramming is a hallmark of tumor development and underlies many of the phenotypic changes observed in cancer cells as they evolve from normalcy to neoplastic growth states. It also plays an important role in cancer cell plasticity during tumor progression and adaptation to therapy. In fact, it has been shown that in cancer, changes in the translation of existing mRNAs are more extensive than changes that occur in transcription downstream of aberrant signaling pathways. Translation at the ribosome is an RNA powered process, governed by sequential interactions between ribosomal, transfer, and messenger RNAs. Ribosomes are not homogeneous, but can be specialized in composition and function, especially in cancer cells. Emerging evidence indicates that alterations in RNA modifications in mRNA, tRNA and rRNA molecules can cause selective translation to drive oncogenesis. For example, in glioblastoma and melanoma, specific upregulation of m⁷G modification in a specific tRNA drives oncogenic transformation due to biased translation of growth-promoting transcripts through a codon-frequency-dependent mechanism. Also, the METTL5 methyltransferase is responsible for m⁶A modification of a specific nucleotide in 18S rRNA. METTL5 is upregulated in hepatocellular cancer where it drives tumor growth and metastasis through enhanced translation of mRNAs involved in fatty acid metabolism, promoting lipogenesis. Furthermore, in acute myeloid leukemia (AML), an overexpressed reader protein IGF2BP2, recognizes select m⁶A modification sites, thereby enhancing the stability and translation of mRNA transcripts involved in glutamine metabolism in support of rapid proliferation and survival of AML cells. Finally, drug-tolerant persister cells in BRAF-mutant melanoma undergo reversible translational reprogramming characterized by preferential translation of mRNAs that contain m⁶A modifications in their 5’-untranslated regions. This subset of mRNAs is enriched in transcripts that drive persistence, and the persister phenotype is reversible upon inhibition of m⁶A modification.

1.4. Impact of Interactions Between Modifications Within and Across RNA Molecules

While these examples highlight individual mRNA, rRNA, or tRNA modification events driving translational reprogramming in cancer, they represent only the tip of the iceberg. Intriguingly, RNA modifications in messenger, transfer, and ribosomal RNAs converge at the translating ribosome with the possibility for positive and negative interactions between modifications. Therefore, a modification in a tRNA can drive oncogenesis in concert or competition with modifications that are present in mRNAs and rRNAs, controlling protein translation. It might not be possible to understand the mechanisms and functions of individual RNA modifications without considering these interactions. For example, one modification type can impact the likelihood of additional modifications of the same or another type being installed within the same molecule as has been reported for m⁵C and m⁶A driving translational reprogramming. Similarly, synergistic m⁵C and m⁶A methylation in the 3’-UTR of p21 (CDKN1A) cooperatively enhance p21 translation in cancer cells, promoting cellular senescence. Also, one type of RNA modification can regulate the cellular activity of the machinery mediating another kind of modification, as has been demonstrated for m⁶A methylation and A-to-I editing. A recent example that highlights the interaction between modifications present on separate RNA molecules is represented by a specific mRNA cytosine acetylation event (ac4C) that prevents the interaction between the cytosine in the mRNA and a modified base in the initiator tRNA, which results in the destabilization of start codon/anticodon base-pairing, impairing translation initiation. There is a substantial gap in understanding such synergistic or antagonistic intramolecular, and especially intermolecular interactions between distinct modifications and their impact on translational regulation. The recognition that dynamically regulated modifications across rRNA, tRNA, and mRNA act in concert to drive oncogenic processes during translation, together with the recent advances in RNA sequencing and modification mapping, create a unique and timely opportunity for a concerted and coordinated effort on RNA modifications in cancer biology to address the goals of this initiative. 

Specific Objectives for This NOFO

Historically, the research community has largely pursued investigations of RNA modifications by studying single RNA species and modification types. However, elucidating how dysregulation of mRNA, tRNA, and rRNA modifications reprograms translation to drive oncogenesis is not likely feasible for any single research laboratory, but will require the combination of expertise in mRNA, tRNA and rRNA biology, translational regulation, and cancer research. To stimulate progress in this emerging field, the RNAMoDO program will support collaborative research projects, preferably using a multi-Principle Investigator (MPI) structure, on how modifications in mRNA, tRNA, and rRNA molecules can drive the oncogenic process through translational reprogramming. To be responsive to the NOFO, each project will also explore the impact of interactions between modifications residing on the same or different RNA molecules during translation.

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

• What are the mechanisms by which biochemical and structural changes caused by modifications in mRNA, tRNA, and rRNA and their interactions contribute to ribosomal heterogeneity in the pre-cancerous state, or during cancer initiation and progression?
• How do different kinds of RNA modifications (within the same or distinct RNA molecules) synergistically or antagonistically interact and combine to alter the properties of RNAs in relation to translational regulation in cancer?
• How do dynamic modifications in mRNA, tRNA, and rRNAs and their interactions alter translation to drive the adaptation of precancerous and tumor cells to cellular stress, such as genomic mutations, hypoxia or chemotherapeutics treatment?
• How do individual or coordinated changes in RNA modifications that drive oncogenesis through translational reprogramming create targetable vulnerabilities?
• How do combinations of dysregulated RNA modifiers (synergistically, or antagonistically) drive translational reprogramming in cancer?
• Are there common mechanisms of crosstalk between RNA modifications during translation in normal cells that become drivers of specific cancer types when dysregulated?
• How can RNA modification mapping and detection approaches be adapted for investigation of crosstalk between modifications underlying the plasticity of translation in cancer initiation and progression?
• Do individual or combinations of RNA modifications in mRNA, tRNA, and rRNA affect the normal and cancer-promoting activity of translation factors during initiation, elongation, or termination of translation?
• Can bioinformatics, computational, structural, or systems biological studies integrate mRNA, tRNA, and rRNA modification data with proteomic studies in cancer to unravel interactions between modifications that drive oncogenesis.

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

To ensure appropriate expertise in mRNA, tRNA and rRNA biology, translational regulation, and cancer research, all applicants are encouraged to use Multiple Principal Investigators (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 research projects as jointly determined to be needed by the awardees and participating NCI staff. Other NCI awardees with relevant expertise may be invited to join the program including its working group(s) as associate members.

Recipients of awards under this NOFO will be expected to participate and present their research progress at an in person 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 NOFO, and applications proposing them will be considered as non-responsive to this NOFO and will be withdrawn:

• Applications that do not propose fundamental investigations in cancer biology;
• Applications that exclusively focus on technology development; and
• Applications that fail to include appropriate expertise in RNA biology and modification, translational regulation and cancer research.

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 NOFO.

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

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs).  These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses.  Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. Intellectual property will be managed in accord with established policy of NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application.  The intramural scientist may submit a separate request for intramural funding as described above. 

Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 How to Apply - 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information. 

• 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 their 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 How to Apply - Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

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 NIH Grants Policy Statement Section 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 NIH Grants Policy Statement 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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply - 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:

Stefan Maas, Ph.D.
National Cancer Institute (NCI)
Email: mailto:[email protected]

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

In addition, due to its focus on collaboration and expertise sharing, this NOFO strongly encourages either the inclusion of significant co-Investigators and/or the use of the multi-PD/PI option. This NOFO is open to all collaborating teams with formal training and expertise in RNA biology and modification, translational regulation and cancer research.

R&R or Modular Budget

All instructions in the How to Apply - Application Guide must be followed.

Principal Investigator Level of Effort: The PI/MPI level of effort must comply with requirements described in NOT-CA-21-096.

The budget is limited to $650,000 in direct costs per year including direct costs for subawards and consortiums. The budget should also include the following components:

Collaborative Activities: Applicants must set aside 8 percent of their annual budget (Direct Costs) in Years 2-5 to support collaborative activities within or beyond the RNAMoDO program. The amount should be presented in the Other Expenses category under the heading "Collaborative Funds". Final decisions for the release of set-aside funds will be contingent upon assessment of the collaborative project’s value for advancement of the program by the RNAMoDO Program Leadership Group.

Travel: Applicants are required to include travel support for an investigator from each U01 research team to attend the RNAMoDO Program annual meeting. In the budget, a travel budget for one trip per year to these meetings must be included. The meeting location varies each year and can be held at an RNAMoDO investigator institution site in the US or at the NCI’s facilities in Rockville, MD.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Biosketch: Ensure that the team’s expertise in RNA biology and modifications, translational regulation, and cancer research are appropriately highlighted.

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 the importance of the RNA modifications and/or related machineries (writers, erasers, readers) being investigated and their impact on translational reprogramming that could underly cancer formation and progression.
• Describe the possible significance of interactions between modifications within or across RNA molecules in the context of the proposed studies.

Approach:

• Describe how the team’s expertise and the proposed concept and experimental approaches will further our understanding of the cellular and/or molecular mechanisms through which RNA modifications reshape the translatome to impact cancer initiation or progression.
• Outline the plans for how potential interactions between modifications within or across RNA molecules will be explored as part of the overall project.
• Address how the project can support the overall vision of this program in looking beyond single modification types and RNA species in the context of translational regulation in cancer.
• Describe how the resources, technologies and infrastructure at the participating institution(s) available to the project can facilitate data integration and sharing across the program and within the scientific community considering the diversity of modification types and RNA species involved.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide. 

Other Plan(s):

All instructions in the How to Apply - 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.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

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 How to Apply - 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 How to Apply - 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 How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. 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. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – 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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply - 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 field of 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 NOFO 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 How to Apply - 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 NCI, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected]. 

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.

For this particular announcement, note the following:

The priority for this NOFO is to stimulate fundamental research in the emerging area of RNA modifications that drive oncogenesis, with a focus on the central role of RNA modifications in translational reprogramming of cancer cells. Another goal is to foster research that explores the crosstalk between RNA modification types within and/or across RNA species in the context of translational regulation in cancer.

. The potential for clinical translation is not a requirement for this NOFO.

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?

Specific to this NOFO: 

• How likely will the proposed studies reveal important mechanisms or concepts concerning how RNA modifications and/or their related machineries (writers, erasers, readers) impact translational reprogramming in cancer?
• How well does the application take into account the possible impact of interactions between RNA modifications across modification types and/or RNA species?
   

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?

Specific to this NOFO: 

• How well does the expertise of the investigative team cover RNA biology and modification, translational regulation and cancer research?
• How well does the application demonstrate that it will foster strong collaboration and interaction between the participating investigators?
   

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? 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?

Specific to this NOFO: 

• How likely can the proposed approach further our understanding of the cellular and/or molecular mechanisms by which RNA modifications drive oncogenesis through translational regulation?
• How well does the approach describe a strategy to explore potential interactions between modifications within or across RNA molecules?
• How well presented is the premise for the investigation of interactions between modifications, while taking into account that this area of investigation may not yet be supported by substantial preliminary data?
• How well does the proposed analysis of RNA modifications across modification types and/or RNA species include considerations for data harmonization, integration and sharing?
   

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 three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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

Not Applicable

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

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 policies and practices, 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

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 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website. 
  • HHS recognizes that NIH 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 NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

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 (HHS) grant administration regulations at 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 purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the 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 NIH as defined below.

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

• 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 Annual Investigators Meeting and other relevant NCI-sponsored meetings and workshops;
• Collaborating with other NCI recipients to advance research on RNA modifications driving oncogenesis through translational reprogramming, including the exploration of crosstalk between modifications within and across RNA molecules;
• 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 NOFO; and
• Facilitating collaboration and validation of experimental concepts and observations on the topic of RNA modifications driving oncogenesis by participating in any scientific working group(s) jointly determined to be needed by the recipients and participating NCI staff.

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 HHS, PHS, and NIH policies.

 

NIH 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 the various activities of the recipients. Specific responsibilities of the NCI Project Scientist(s) will include, but will not be limited to
 

• Monitoring the scientific and technical directions of the RNAMoDO program;
• Recommending approval of changes in the research directions of the program;
• Assisting both individual award recipients as well as any scientific working group(s) jointly established by the program with defining objectives and avoiding unwarranted duplications of effort;
• Facilitating collaborative research efforts between recipients and associate members;
• Serving as a resource for recipients, particularly in making them aware of other ongoing NCI activities that may be relevant to the study of RNA modifications driving oncogenesis through translational reprogramming;
• 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 approaches and best practices developed by recipients to study RNA modifications in the context of translational regulation, 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; and
• Make final recommendations for the release of set-aside funds, based on the recommendations of the RNAMoDO Program Leadership Group.

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:

The Program Leadership Group will serve as the primary governing body of the RNAMoDO program. The Program Leadership Group will be jointly established by all the awarded PDs/PIs of the RNAMoDO program and the NCI Program Staff members. The RNAMoDO Program Leadership Group will provide strategic coordination for the activities of the RNAMoDO recipients and the RNAMoDO program overall.
Details on the composition, functions, and responsibilities of the RNAMoDO Program Leadership Group are the following:
Program Leadership Group: The RNAMoDO Program Leadership Group will be composed of the following voting members:
 

• PD(s)/PI(s) representing the RNAMoDO U01 awards; and
• An NCI Project Scientist

Each voting member will have one vote.
Additional NIH staff may participate in RNAMoDO Program Leadership Group meetings as non-voting members as needed (for example to provide additional expertise).
Additional non-voting members may participate on the RNAMoDO Program Leadership Group in an advisory capacity on an as-needed basis and decided by the existing voting committee members.
The Chair of the RNAMoDO Program Leadership Group (who cannot be NIH staff) will be selected by the RNAMoDO Program Leadership Group. The RNAMoDO Program Leadership Group will meet in association with the annual PI meeting and via teleconference as needed.
Primary responsibilities of the RNAMoDO Program Leadership Group include, but are not limited to, the following activities:
Establishing procedures for the solicitation, evaluation and recommendation to awardees of collaborative/joint projects to be pursued with support of the set-aside funds from individual U01 awards.
 

• Formulating policies and procedures for data collection, integration, and harmonization.
• Identifying impediments to success and strategies to overcome them.
• Helping with the planning of major events (such as the annual meeting).
• Identifying opportunities for sharing techniques, materials, information, and tools.
• Facilitating communication and fostering collaboration across the program.
• Ensuring RNAMoDO leverages existing NIH resources and programs.
• Evaluating collaborative activities, and providing feedback to the NCI Program Staff.
   

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 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 HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Consistent with the 2023 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 Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs 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 2 CFR Part 200.301.

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]

Stefan Maas, Ph.D.
National Cancer Institute (NCI)
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 2 CFR Part 200.