Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Dental and Craniofacial Research (NIDCR)
Funding Opportunity Title	Targeting Co-dependent Molecular Pathways in Oral Cancer (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	RFA-DE-15-004
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.121
Funding Opportunity Purpose	The purpose of this Funding Opportunity Announcement (FOA) is to support multi-disciplinary projects aimed at the development of new targeted and effective therapies through systematic use and leveraging of recently identified genomic abnormalities and attendant changes in gene and/or protein expression profiles in human oral cancer samples. The goal of the FOA is the identification of co-dependent survival and proliferation pathways in oral cancer cells and the elucidation of potential signaling pathways that can be targeted with combination therapy approaches. This initiative requires collaboration of multi-disciplinary research teams that include cancer biologists, computational biologists, model system specialists and/or screening assay specialists. The emphasis will be on the conceptual phase of target identification and exploration including proof-of-concept phase.

Posted Date	April 22, 2014
Open Date (Earliest Submission Date)	July 25, 2014
Letter of Intent Due Date(s)	July 25, 2014
Application Due Date(s)	August 25, 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)	Not Applicable
Scientific Merit Review	January, 2015
Advisory Council Review	May, 2015
Earliest Start Date	July 2015
Expiration Date	August 26, 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 objective of this Funding Opportunity Announcement (FOA) is to identify oral cancer cell-specific novel therapeutic targets using approaches that leverage existing data sets combined with novel computational approaches, clinically relevant model systems and molecular screening/analyses. This initiative requires the formation of highly collaborative multi-disciplinary research teams that include cancer biologists, computational biologists, model system and/or screening assay specialists. The expected outcome of studies supported through this FOA is the identification of a set of co-dependent therapeutic targets that could, in turn, be analyzed in pre-clinical models.

Cancers of the oral cavity and oropharynx represent the majority of head and neck cancers with ~45,000 new cases diagnosed each year in the U.S. The 5-year survival rate of oral and oropharyngeal cancer patients is ~60% and has improved only marginally during the past few decades. The impact of current cytotoxic therapies for oral cancer is limited by disease recurrence and resistance to therapy. In addition to the limited survival, some of the major problems with the current treatment modalities for oral cancers include their lack of specificity and the consequent cytotoxicity to normal cells which lessens their therapeutic effectiveness. Furthermore, current treatment regimens including surgery, radiation, and chemotherapy often lead to morbidity that reduces the patient's quality of life. Given the cytotoxic and non-specific nature of current oral cancer therapies and their limited efficacies, there is a tremendous need for development of targeted and effective therapies that have fewer and less severe unwanted side effects and minimal negative effects on the quality of life of individuals.

One of the major obstacles to targeted cancer therapies with minimal side effects is our limited understanding of all the molecular alterations that lead to the evolution of a normal cell into a cancer cell and its ability to survive in distant metastatic sites. However, advances in genomics, bioinformatics, and high throughput screening methods have provided us with the tools to identify molecular alterations in cancers and helped us better understand abnormalities of signaling pathways in cancer cells. Such discoveries are expected to provide crucial targets for development of cancer therapeutic agents. To this end, a variety of programs are producing comprehensive datasets that catalog cancer genomes and their representative mutation profiles, epigenomes and transcriptomes. Some of the major initiatives that have provided large datasets for specific tumor types include the following initiatives: TCGA (http://cancergenome.nih.gov/), TARGET (http://www.target.cancer.gov/), Cancer Genome Characterization Initiative (CGCI, http://cgap.nci.nih.gov/cgci.html), and the International Cancer Genome Consortium (ICGC, http://www.icgc.org/).

Preliminary analyses of the genomes of various tumor types have begun to provide information on the complexity of the pathways involved in cancer formation, differences in the genetic make-up of cancers with different etiologies (e.g., virus-induced versus non-virus-induced cancers) and heterogeneity of the tumors at the genetic level. While progress has been made in the preliminary genomic, epigenomic and transcriptomic characterization of human oral cancers, considerable knowledge gaps and bottlenecks remain in areas such as: elucidation of oral cancer-specific signaling pathways, integration and exploitation of -omic analyses towards mechanism-based therapies for oral cancer, and systematic validation of potential cancer specific signaling pathways that are druggable . To expedite the utility of the comprehensive data sets in identifying the molecular characteristics of oral cancers, novel approaches are needed that consider complexity of the cancer formation process and the rewiring of signaling pathways in a global/systems biology context. In addition, recent mathematical modeling studies based on outcome data from cancer clinical trials also suggest that targeted simultaneous combination therapy is superior to mono-therapy or sequential therapy. This FOA will support multidisciplinary team research aimed at identifying novel signaling pathways that would inform therapeutic strategies based on the genomic complexity of oral cancers using clinically relevant model systems.

Recent data indicate that cancer cells become dependent on distinct molecular pathways that involve growth factor signaling, DNA repair and cellular metabolism and such pathways provide potential therapeutic target. Targeted and rational therapies based on distinct signaling abnormalities of cancer cells have the potential to supersede current therapies with their dose limiting toxicities. The dependency of cancer cells on various specific cellular signaling mechanisms has been described as oncogene addiction, synthetic lethality, genetic dependency and tumor suppressor hypersensitivity depending on the context. Some examples of the above mentioned phenomena include: (i) hypersensitivity of BRCA1 mutant breast cancer cells to inhibitors of the DNA repair protein PARP1; (ii) sensitivity of p53-deficient cells to Check point kinase 1 (CHK1) inhibition; and (iii) synthetic lethality of cancer cells exposed to Metformin and glucose withdrawal. We intend to support studies aimed at identifying such cancer cell vulnerabilities using medium to high throughput strategies in clinically relevant model systems.

Examples of projects and approaches that are of interest include, but are not limited to those listed below:

• Utilization of novel or improved genomics, bioinformatics and/or systems biology methods coupled with in vitro and/or in vivo testing in clinically relevant model systems that will lead to a better understanding of the multiple signaling processes in oral cancer that are targetable for cancer therapy;
• Determination of complex dependencies that include oncogene addiction, tumor-suppressor hypersensitivity and metabolic dependencies in oral cancer and the identification of combinations of targets which could be exploited for therapeutic interventions;
• Determination of targets/target combinations suitable for synthetic lethality-based approaches;
• Determination of the underlying mechanisms and/or identification of novel biological modulators that could be exploited for therapeutic targeting;
• Utilization of novel, high-throughput, and cost-effective screening protocols (e.g., RNA interference) in clinically relevant model systems aimed at the identification of potential targets and/or providing functional characterization of potential targets identified by other approaches;
• Probe development for potential targets (the choice of potential targets must be well justified; for example, it may stem from bioinformatics/systems biology characterizations or experimental validation); and
• Quantitation of cellular measurements in genetically characterized cancer cell lines using a range of potential perturbagens/biologically active agents combined with bioinformatics analyses to predict responses (e.g., genotypic determinants of drug sensitivities) and testing these predictions in appropriate in vitro and/or in vivo models.

Studies with a high potential to reveal novel targets and/or target combinations or cancer dependencies that are relevant to cancers of the oral cavity are strongly encouraged. It is expected that these goals can be maximized by using high-throughput approaches. Studies should allow for prioritization of the potential utility of multiple candidates as targets in a given category.

Studies aimed at expanding the definition of genetic alterations that are deemed "druggable for therapeutics will be of particular interest. Well-studied targets, such as kinases, phosphatases, or growth-factor receptors are of limited interest except in specific, justified circumstances (such as to clarify their effects on other potential novel targets or as components in strategies aimed at combinations of targets).

This FOA is focused on the conceptual phase of target identification and determination including proof-of-concept for oral cancer. Thus, further development of specific therapeutic approaches based on identified potential targets or small molecule modulators is beyond the scope of this FOA. Nevertheless, applicants are encouraged to consider how such future developments could take place and summarize briefly their translational expectations in the application.

Applicants are strongly encouraged to plan for experimental approaches and bioinformatics solutions that would facilitate sharing data, protocols, and results with the research community at large. For example, research protocols must be specific and detailed enough that they would allow for reproducibility in other laboratories. Also, it is expected that data analysis pipelines (i.e., sequences of bioinformatics algorithms applied across multiple data sets intended to generate an integrated, comprehensive analysis of the input) will be defined and published (either on the project’s web site or in peer-reviewed manuscripts) in sufficient detail to permit faithful replication of an analysis. For these reasons, it is highly desirable that applicants include in their plans the use of an open standard Workflow Management System (e.g., Taverna, http://www.taverna.org.uk/) to describe bioinformatics protocols/workflows to be developed.

Applicants are encouraged to propose novel 3-D culture systems with high to medium throughput capabilities as appropriate. Studies that use established oral cancer cell lines that have limited correlation to the genetic makeup of human oral cancers and studies that propose routine toxicity or growth assays that do not mimic the micro-environment are discouraged unless well justified.

For all projects, applicants are encouraged to utilize or develop standard processes (workflows) that include consideration of such factors as: data quality, statistical significance required for interpretability of the results, throughput, and unit costs. The workflows should also include defined approaches for validating results.

Research projects must have multidisciplinary teams composed of at least one computational biologist and one or more experts in the following fields but not limited to: cancer biology, screening assays, synthetic chemistry, chemical biology, phramacology, and cancer model systems.

Models used in experimental studies must have the corresponding genetic background cataloged for oral cancers, e.g., functional single nucleotide polymorphisms, DNA segment copy number alterations and/or mutations. Such models may include cell lines or xenografts from patients. Well-justified novel mouse model systems for oral cancer that are already available also may be considered provided they replicate the genetic and phenotypic characteristics of human oral cancers. However, established cancer cell lines may be proposed only if there is sufficient information documenting that these cell lines maintain phenotypic attributes of oral cancer and their signature of molecular abnormalities (at the genetic and other levels) and matches respective cancer signatures established for oral cancer biospecimens from patients.

If libraries of small molecules are used, applicants must consider various options and selection choices to maximize structural and chemical diversity of compounds to be tested. For this reason, the development of new small molecule libraries is encouraged whereas studies proposing solely to use the few commercially available small molecule libraries are not allowed.

Applications that propose the following will be deemed non-responsive:

• Studies that propose only the sequencing (exome or whole genome), proteomic, and epigenomic analysis of primary oral cancer samples;
• Studies focused only on the development or characterization of new genetic mouse models to study gene function;
• Studies aimed only at developing or characterizing mouse model systems for oral cancer will not be supported unless used for validating drug targets;
• Studies that propose the identification of diagnostic or prognostic biomarkers of oral cancer;
• Testing of well-studied targets including kinases, phosphatases, apoptosis inhibitors, growth factor receptors, unless used in screens for identifying dependencies or synthetic lethal interactions with novel targets;
• Studies that involve testing of conventional non-specific therapeutics (e.g., replication inhibitors, non-specific epigenetic modulators, and radiation);
• Development of drugs beyond the target identification, selection, lead discovery and early validation phases are not within the scope of this FOA;
• Studies that focus solely on specific drug entities and their targets;
• Use of cell lines or xenografts without adequate experimental validation indicating that they include the relevant molecular aberrations found in human oral cancers with the corresponding phenotypes are not allowed. For example, unsuitable as biological models for this FOA are: a) established oral cancer cell lines that have been extensively propagated (unless detailed documentation is available that they match the attributes of human oral cancers); or b) xenografts established through old protocols that involved a cell passage through a tissue culture stage, no matter how transient;
• Studies that focus on specialized cancer cell populations (e.g., cancer stem cells) are not allowed given the paucity of molecular data in such populations;
• Studies that focus merely on in silico approaches without validation in appropriate model systems; and
• Studies proposing clinical trials of any phase trials will not be supported by this FOA.

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 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. NIDCR intends to commit up to $3 million in FY 2015 to fund 3-4 awards.
Award Budget	Application budgets are limited to $600,000 per year in direct costs and should reflect the actual needs of the proposed project.
Award Project Period	4 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. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from 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.

The use of the Multiple PD/PI model is strongly recommended for this FOA.

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:

Yasaman Shirazi, PhD
Chief, Scientific Review Branch
NIDCR, NIH
6701 Democracy Boulevard, Suite #662
Bethesda, Maryland 20892
(Courier 20817)
Telephone: 301-594-5593
Fax: 301-480-8303
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this specific FOA, the Research Strategy section is limited to 12 pages.

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.

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

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 PDs/PIs are expected to designate at least 15% effort (at least 1.8 calendar months/year) that reflects their role in the proposed multidisciplinary teams.

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:

Research Strategy:

Investigators should include the following in the Research Strategy section:

• Clinical relevance of the model systems used in the research strategy to human cancers of the oral cavity and the observed molecular changes in such cancers;
• Validity and advantages of the omics based data sets used in the analyses to identify novel targets for therapy;
• Novelty of the proposed model systems, experiments and analyses and the improvements and/or advantages in comparison to those currently available;
• Expected milestones and potential decision points for alternate approaches if milestones are not achieved.

In addition, the research strategy should be supported by:

• Rigorously collected preliminary data and well-designed experimental plans that support the rationale (scientific premise);
• Reliableand clearly defined scientific findings that support the rationale (scientific premise);
• Inclusion of appropriate statistical plans, power calculations and controls;
• Inclusion of rigorous methodological approaches that minimize potential bias when applicable (i.e., methods for randomization/stratification, inclusion of a plan for reporting all results, negative or positive, addressing missing data etc.);
• Appropriate skills in the investigative team for rigorous collection, analysis, and interpretation of data.

Multiple PD/PI Leadership Plan: Applicants should include a Collaboration Plan within the Multiple PD/PI Leadership Plan that describes the roles, the responsibilities, and the working relationship of the identified PD/PIs in the multidisciplinary team. Applicants should also describe the strengths of the multiple PD/PI team in implementing the proposed experimental plans and its appropriate alignment with the proposed research strategy and the goal of the FOA to identify oral cancer cell-specific novel therapeutic targets using approaches that leverage existing data sets combined with novel computational approaches, clinically relevant model systems and molecular screening/analyses.

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.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report 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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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? Is the rationale (scientific premise) supported by rigorously collected preliminary data and well-designed experimental plans? Is the rationale (scientific premise) supported by reliable, transparent, and clearly defined scientific findings?

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? Are all appropriate skills present in the investigative team to rigorously collect, analyze, and interpret the data for the proposed study? Is the multi-disciplinary expertise of the team and their prior accomplishments aligned with the proposed research strategy and the FOA goal to identify oral cancer cell-specific novel therapeutic targets using approaches that leverage existing data sets combined with novel computational approaches, clinically relevant model systems and molecular screening/analyses.? Will goal of the FOA to identify oral cancer cell-specific novel therapeutic targets using approaches that leverage existing data sets combined with novel computational approaches, clinically relevant model systems and molecular screening/analyses be achievable with the level of effort proposed by PDs/PIs?

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? Are appropriate statistical plans, power calculations, and controls included? Are rigorous methodological approaches that minimize potential bias included? Are the bioinformatics and/or modeling approaches proposed for the identification of novel targets using oral cancer genomics data based on sound rationale and valid data sets? Are the investigators using clinically relevant and validated model systems that relate to molecular changes in human oral cancer samples?

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 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? Does the environment have the appropriate infrastructure to allow data sharing/deposition, collaboration, and dissemination of research findings (examples for this FOA include but are not limited to the following: bioinformatics data analysis core, high throughput screening capabilities, access to clinical samples for validation, database support etc.)

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 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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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 children 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 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

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

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 NIDCR, 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.

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

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 submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Dental and Craniofacial Research Council. 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.

Cooperative Agreement Terms and Conditions of Award

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 the research plan and goals;
• Overseeing the execution of the projects and coordinating/overseeing research design;
• Ensuring compliance with the mandatory regulations (including protection of human subjects);
• Overseeing establishment and maintenance of appropriate quality control procedures;
• Overseeing final data analysis and interpretation and preparation of publications;
• Cooperating with NIDCR programmatic, technical and administrative staff;
• Administratively managing the U01 award;
• Participating in monthly periodic teleconferences (as needed); and

Ensuring and overseeing the timely sharing of results, resources, methods etc. with the scientific community.

• The Program Directors/Principal Investigators agree to accept assistance, coordination, cooperation and participation of NIDCR staff in scientific management of the project in accordance with the terms formally and mutually agreed upon prior to the award.
• Publications: The Program Director/Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by members of the cooperative agreement award and supported in part or in total under this Agreement. Publications or oral presentations of work performed under this Agreement are the responsibility of the Program Director/Principal Investigator and will require appropriate acknowledgement of NIDCR support.
• All PDs/PIs on a U01 award will be expected to maintain significant effort commitment not smaller than that stated in the application (at least 1.8 calendar months/year during the funded period of the project).
• Awardees will be expected to develop and implement common, uniform standard operating procedures (SOP) and technical formats for depositing data into public databases. It is expected that these data reporting solutions will be compliant with generally accepted publicly available standards. Human subject characterization data (i.e. clinical data ) shall be described using cancer Biomedical Informatics Grid (caBIG, https://cabig.nci.nih.gov/) Common Data Elements registered in the cancer Data Standards Repository. Data generating methods and analysis algorithms shall be described in sufficient detail to enable duplication by other investigators.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

• A designated NIDCR Program Director(s) acting as a Project Scientist(s) will have the following responsibilities:
• The NIDCR Project Scientist/Program Official will serve as a liaison/facilitator between the awardee and other government agencies, and will serve as a resource of scientific and policy information related to the goals of the awardee's research. The NIDCR Project Scientist/Program Official will facilitate coordination of project activities during the course of the project. The NIDCR Project Scientist/Program Official will assist the awardee with access to other NIDCR-supported resources and services. The NIDCR Project Scientist/Program Official will also be responsible for:
• Monitoring progress of the program as a whole and the specific studies conducted;
• Negotiating project specific milestones with grantees during the funding phase;
• Providing policy assistance and feedback to the awardees as appropriate;
• Conducting periodic site visits or discussions with awardee research teams as needed;
• Facilitating interactions/collaborations between the awardees and other NIH-sponsored programs, investigators, or organizations that may contribute to the project goals; and
• Monitoring the adherence of the awardees to the approved data sharing plans.
• 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.
• The NIDCR will adjust funding, withhold, suspend, or terminate the support to the awardee if the team is unable to meet the negotiated milestones set forth in these Terms and Conditions of Award or the performance of the team is deemed to be significantly low that the aims will not be met within the time frame of the cooperative agreement. Continuous funding will depend upon meeting milestones negotiated for the projects.

Areas of Joint Responsibility include:

• None; all responsibilities are divided between awardees and NIH staff as described above.

Additional notes:

NIDCR will assemble an External Expert Panel to review progress of the projects on an annual basis and provide input to enhance performance of the projects as appropriate. Awardees are expected to plan and budget for an annual meeting either at the NIH or at a national scientific meeting venue (e.g. AACR meeting) to discuss progress of their projects.

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 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]

Sundar Venkatachalam, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4812
Email: [email protected]

Yasaman Shirazi, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-5593
Email: [email protected]

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [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.