Key Dates

Related Announcements

NOT-CA-23-074 - Notice of Correction to Agency Routing Identifier for NOT-CA-23-060 "Notice of Special Interest (NOSI): RNA Modifications in Cancer Biology".

PA-20-195 - NIH Exploratory/Development Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PAR-23-058 - NCI Small Grants Program for Cancer Research for Years 2020, 2021, and 2022 (NCI Omnibus R03 Clinical Trial Optional)

RFA-CA-23-002 - Innovative Molecular and Cellular Analysis Technologies for Basic and Clinical Cancer Research (R61 Clinical Trial Not Allowed)

RFA-CA-23-003 - Advanced Development and Validation of Emerging Molecular and Cellular Analysis Technologies for Basic and Clinical Cancer Research (R33 Clinical Trial Not Allowed)

RFA-CA-23-014 - Development of Innovative Informatics Methods and Algorithms for Cancer Research and Management (R21 Clinical Trial Optional)

RFA-CA-23-015 - Early-Stage Development of Informatics Technologies for Cancer Research and Management (U01 Clinical Trial Optional)

Issued by

National Cancer Institute (NCI)

Purpose

Through this Notice of Scientific Interest (NOSI), the National Cancer Institute intends to stimulate research on the role of RNA modifications in the area of cancer biology. Despite the recognition that RNA modifications and editing exert a substantial impact on gene expression and function, there is a lack of mechanistic insights into the dynamic regulation of RNA modifications and their de-regulation as drivers of cancer formation. A better understanding of the extent, diversity, and crosstalk between different types of RNA modification, and the elucidation of the molecular players that read and interpret the modification code are needed to reveal the mechanisms of RNA modifications that underly cancer formation and the cancer phenotype.

Background

RNA Modifications: The conversion from genotype to phenotype proceeds through transcription of RNA molecules that undergo co- and post-transcriptional processing (splicing, capping, polyadenylation) before exerting their functions as RNAs or as proteins after translation. An additional layer of genetic information has been emerging with the widespread detection of chemical modifications in RNA molecules. To date, more than 170 types of RNA modifications have been reported, including N⁶-adenosine methylation (m⁶A), adenosine to inosine (A-to-I) deamination, cytosine to uracil (C-to-U) deamination, N¹-adenosine methylation (m¹A), 5-cytosine methylation (5mC), pseudouridylation (?), and ribose 2 O-methylation. There is a growing list of RNA modifications found in coding and non-coding RNAs that impact their biological function as they often lead to alterations in RNA stability, folding, interaction, translation, localization, and subsequent processing. However, insights into the molecular machineries that deposit and remove, as well as recognize and interpret these modifications within the cell are available for only a few modifications. And even for those types of modifications where writers, erasers, and readers have been identified, such as N⁶-adenosine methylation, little is known about their regulation, their cooperation or competition with other RNA modification and processing events, and how they become de-regulated in disease.

Since some chemical moieties can be added and removed in a dynamic fashion on short time scales, approaches for the quantitative, cell- and transcript-specific mapping of RNA modifications are critical. Some types of RNA modification alter base-pairing behavior (A-to-I and C-to-U base-modification editing) or chemical properties (pseudouridylation, 5mC) of the RNA molecule and can thus be directly detected and mapped through sequencing-based approaches. For others, such as m6A, detection to date relies on indirect methodologies such as immunoprecipitation of modified RNAs with modification-specific antibodies or bulk chromatography and mass spectroscopic approaches. The majority of RNA modifications are difficult to detect since methodologies for transcriptome-wide mapping and quantitative determination of modification rates at the single nucleotide level are not available. This further substantially impedes the investigation of their functional roles and disease relevance.

RNA Modifications in Cancer: There is emerging evidence that RNA species become hyper-, hypo- or mis-modified in cancer, and that the over- or under-expression, mutation, or deletion of molecular players in RNA modification can be linked to the cancer phenotype. For example, aberrant deposition, removal, and recognition of N⁶-adenosine methylation (m6A), the most predominant type of RNA 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 or the METTL3 methyltransferase can lead to differentiation blockage and leukemogenesis. They may regulate distinct sets of targets and thereby display oncogenic roles in the same cancer cell context. In glioblastoma (GBM), the METTL3 methylase has been shown to function as a tumor suppressor, while the demethylase FTO and the m6A reader ALKBH5 are associated with poor clinical outcome and enriched in glioma stem cells, and knock-down of ALKBH5 in glioma stem cells inhibited proliferation and tumorigenesis. The levels of m6A within mRNAs of hepatocellular carcinoma tissues were found to be decreased due to the downregulation of the methylase complex and associated with metastasis and worse prognosis. Overall, the m6A machinery of writes, erasers, and readers is deregulated in a range of human cancers and functions as either oncogenes or tumor suppressors, suggesting a substantial interaction between m6A modification and the development of human cancers. Nonetheless, mechanistic insights into the molecular events that drive these changes during cancer formation are largely lacking.

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 through A-to-I editing in mRNAs, aberrant editing can directly impact the proteome and has been shown to be a source of cancer protein heterogeneity and the production of neoantigens. Patterns of overediting as well as underediting have been observed in cancer, affecting mRNAs as well as non-coding miRNA transcripts. For several other types of RNA modifications, including pseudouridine, 5-methylcytosine, 1-methyladenosine, and 7-methylguanosine, oncogenic or tumor suppressor functions have been ascribed to molecular players involved. However, there is little understanding about the dynamic regulation and functional roles of these modifications in cancer biology.

Research Objectives

Through this NOSI, the National Cancer Institute intends to stimulate research on the role of RNA modifications in cancer biology by supporting small investigator-initiated research grants. Gaining a better understanding of the roles of RNA modifications in cancer biology requires investigations into the what, where, when, how, and why of the processes that are inducing, regulating, and responding to these modifications. The proposed studies in response to this NOSI should be designed to generate key data as the foundation for future hypothesis-driven R01-type applications. This NOSI is a reissue of NOT-CA-22-003.

Research areas of interest for this NOSI include but are not limited to:

• Novel methodologies and tools for the detection, mapping, and quantification of chemical modifications of RNA molecules in cancer, in vitro and in vivo
• Improvements to existing methodologies to study RNA modifications, such as validation studies, increase in throughput, sensitivity, or utility
• Studies that establish mechanistic links between RNA modifications and the cancer phenotype using existing clinical resources
• Investigating RNA modification-driven cancer formation in mammalian and non-mammalian Research Organisms
• Investigating the dynamics of one or multiple types of RNA modifications driving cancer formation
• Characterization of writers, erasers, and readers of modifications and their cancer-associated de-regulation
• Understanding crosstalk between two or more modes of RNA modification during cancer formation
• Identification of tumor cell vulnerabilities resulting from cancer-related changes in RNA modifications
• Identification of RNA modification signatures that can serve as potential biomarkers in cancer biology
• Mechanisms of how RNA modification becomes de-regulated in cancer

Application and Submission Information

This notice applies to due dates on or after June 13, 2023, and subsequent receipt dates through January 8, 2026.

Submit applications for this initiative using one of the following Notice of Funding Opportunities (NOFOs) or any reissues of these announcements through the expiration date of this notice.

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

• For funding consideration, applicants must include NOT-CA-23-060 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Although NCI is not listed as a Participating Organization in all the NOFOs listed above, applications for this initiative will be accepted.

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

Inquiries

Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

Scientific/Research Contact(s)

Stefan Maas, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6230
Email: stefan.maas@nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Amy R. Bartosch
National Cancer Institute(NCI),
Telephone: 240-276-6375
Email: amy.bartosch@nih.gov