Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Cancer Institute (NCI)

Funding Opportunity Title

New Approaches to Synthetic Lethality for Mutant KRas-Dependent Cancers (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

None

Funding Opportunity Announcement (FOA) Number

PAR-14-314

Companion Funding Opportunity

None

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.396 

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications for projects to identify targets whose inhibition would induce synthetic lethality in cancers dependent on the expression of mutant KRas alleles. Despite recent advances in understanding the structural and biological complexities of mutant Ras proteins, the development of appropriate and effective methods to inhibit mutant Ras-dependent cancers has been hindered by the inability to directly target mutant Ras and the complexity of Ras processing, effector, and regulatory networks. Through this FOA, the NCI seeks to stimulate research that uses advanced or improved approaches for synthetic lethality screens that have greater specificity, reproducibility, and activity in physiologically relevant model systems than those used previously in first generation screening approaches. This FOA serves to engage extramural investigators in the mission of the NCI Frederick National Laboratory for Cancer Research (FNLCR) RAS Program to find ways to target Ras-dependent cancers. Investigators supported by this FOA will form a network to interact closely with the FNLCR RAS Program, actively exchange results across the network, and participate in cross-validation of potential targets identified by other awardees.   

Key Dates
Posted Date

August 7, 2014

Open Date (Earliest Submission Date)

October 10, 2014

Letter of Intent Due Date(s)

30 days before the application due date(s)

Application Due Date(s)

November 10, 2014; July 8, 2015, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

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

February/March 2015; October/November 2015

Advisory Council Review

May 2015; January 2016

Earliest Start Date

July 2015; April 2016

Expiration Date

July 9, 2015

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.


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Table of Contents

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

Part 2. Full Text of Announcement
Section I. Funding Opportunity Description

The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications for projects to identify targets whose inhibition would induce synthetic lethality in cancers dependent on the expression of mutant KRas alleles. Despite recent advances in understanding the structural and biological complexities of mutant Ras proteins, the development of appropriate and effective methods to inhibit mutant Ras-dependent cancers has been hindered by the inability to directly target mutant Ras and the complexity of Ras processing, effector, and regulatory networks. Through this FOA, the NCI seeks to stimulate research that uses advanced or improved approaches for synthetic lethality screens that have greater specificity, reproducibility, and activity in physiologically relevant model systems than those used previously in first generation screening approaches. This FOA serves to engage extramural investigators in the mission of the NCI Frederick National Laboratory for Cancer Research (FNLCR) RAS Program to find ways to target Ras-dependent cancers. Investigators supported by this FOA will form a network to interact closely with the FNLCR RAS Program, actively exchange results across the network, and participate in cross-validation of potential targets identified by other awardees.

Background and Rationale

RAS genes and mutations: Oncogenic mutations in RAS genes are thought to be essential in the development of approximately 30% of all cancers, and particularly important in those arising in the pancreas, colon, and lung. In FY2013, the NCI launched the RAS Program at the FNLCR to take advantage of current science and technologies to build effective approaches to target mutant Ras-dependent cancers, a task that has historically been elusive. One of the priorities set forth in the initiative for the FNLCR RAS Program focused on engaging researchers to use novel synthetic lethal screens and approaches to identify proteins essential for the survival of cancer cells that have mutated KRAS genes.

Ras proteins are the most frequently mutated oncogenes in cancer. Although each Ras protein (KRas, NRas, HRas) can be mutated to drive cancer development, mutation of a single gene product is often favored in a particular cancer type and each isoform has a distinct mutation profile. Mutations in KRas are more common than those in NRas or HRas, and occur predominantly in cancers of the pancreas, lung, and colon. Because of the more frequent occurrence of KRas mutations in human cancers, this FOA focuses on cancers with these mutations.

Single-base substitution mutations in Ras proteins often occur in codons 12, 13, or 61. These mutations render Ras proteins insensitive to the hydrolyzing activity of GTPase-activating proteins (GAPs), and thus mutant Ras proteins remain chronically active. Although the consequences of specific mutations, beyond sustained activation, are unclear, the notion that specific mutations may have unique or preferential interacting partners and signaling effector pathways is becoming clearer. This FOA focuses on the predominant mutant KRas alleles (G12C, G12D, G12V, and G13D).

Challenge of targeting mutant KRas-dependent cancers: Targeting Ras directly has been challenging because of its extremely high affinity for GTP and the complexity of its processing, effector and regulatory networks. Although approaches to inhibit Ras-mediated effector pathways seem plausible, a plethora of effectors have been identified that are involved in autocrine and/or paracrine regulation of proliferation, growth, metabolism, differentiation, and survival. Furthermore, cancer cells driven by oncogenes gain additional dependencies on other genes, proteins, and/or pathways deemed non-essential in normal cells lacking the oncogenic driver. Identifying and exploiting these new dependencies underlie the premise of synthetic lethality.

Synthetic interactions and synthetic lethality: Synthetic genetic interaction is a concept first recognized and studied in genetically tractable organisms. Synthetic interactions, which are common in biology, describe a state in which a combination of two mutations produces a phenotype that is not seen with either mutation alone. The interaction between the mutated gene products may occur in parallel dependent pathways or non-parallel pathways that intersect at a predicted or unexpected node. This concept has potential applications in cancer, where continued tumor viability is dependent on one or more mutations that occur during cancer development and progression. If a complementary biochemical event can be identified that will induce lethality when inhibited in the presence of one of the essential cancer mutations, this biochemical event becomes a potential target for future drug development. Typically, the identification of synthetic lethal interactions has been made by using RNAi libraries to knockdown specific mRNAs and comparing the responses in isogenic cells that differ in expression of only one cancer mutation.

Challenges of synthetic lethal screens: A number of circumstances can confound the simple prediction of synthetic lethality. These include differences in the genetic, epigenetic, and phenotypic heterogeneity of the cell population; differences in the local soluble, cellular, and physical microenvironment; and differences in screening formats. The results of published synthetic lethal screens in cells dependent on mutant KRas expression are particularly confusing. These screens have relied primarily on RNAi libraries and small numbers of selected cell lines. Potential synthetic lethal hits with mutant KRas have often not been reproduced in confirmatory studies in other laboratories. It is unknown whether allele-specific mutant KRas synthetic lethal partners and their regulatory and effector pathways vary with cancer type or are influenced by co-mutations and genetic heterogeneity. Thus, this lack of reproducible target identification may reflect contextual differences such as differences in cancer type, mutant KRas allele, or culture system; technical variations such as use of an arrayed versus a pooled format, depth of RNAi coverage, or off-target effects; and/or unexplored differences between strains of similarly named cell lines. In addition, these screens have not led to easy connections to experiments in organoid cultures or tumor-bearing animals. This raises the possibility that synthetic lethality screens performed using first-generation RNAi screening methodology with in vitro adherent monolayer cell line cultures oversimplified the biology of cancer cells and the selective pressures exerted the physical and soluble microenvironment that influences tissue architecture, cell-cell interactions, and cell-extracellular matrix interactions.  

Next generation synthetic lethal screens: Since the publication of the initial mutant KRas synthetic lethal screen results, considerable progress has been made in the approaches that can be used for these types of screens. Recently, libraries have been prepared with deeper coverage of RNAi reagents for each mRNA. Some new libraries feature well-characterized RNAi's for each mRNA. New types of gene ablation strategies, such as ­transcription activator-like effector nucleases (TALENs), clustered regularly interspaced short palindromic repeats (CRISPRs), or zinc finger nucleases (ZFNs), have also been developed and used effectively to knockdown protein levels more efficiently and with greater specificity than seen with initial RNAi approaches. In addition, considerable advances have been made in cell culturing techniques, and in 3-D culture, organoid, tissue, and direct tumor screening systems. 

The RAS Program and FNLCR: The RAS projects ongoing at FNLCR are focused on establishing the genetic profiles of cells that might be responsive to mutant KRas ablation, identifying ways to target KRas directly by modifying its activity, its interaction with effectors or localization, and by identifying antigens useful for immune-based or nanoparticle-based therapies. The identification of synthetic lethal targets in KRas-driven human cancers is complementary to the core projects at the FNLCR. Additional information on these projects can be found RAS Program Hub. The NCI-FNLCR team has assembled a panel of RAS and RAS-related plasmids that are available for the research community (as described RAS reagents).  Additionally, isogenic cells lines can be obtained from the NCI-FNLCR team for research initiated in response to this FOA or for other studies.  A variety of other cell lines are being used for studies at FNCLR. Genotypic information and how to obtain such cell lines are provided RAS cell lines.

Scope of the FOA and Specific Requirements

The scope of this FOA is to identify novel targets whose inhibition would induce synthetic lethality in human cancers dependent on the expression of allele-specific mutant KRas. To allow for cross-validation and direct comparisons, it will be necessary to fully define the context within which the target is vulnerable. The studies should focus on one or more of the four most frequently observed alleles (G12C, G12D, G12V, G13D) in one or more of the predominant mutant KRas-dependent cancers e.g., pancreas, lung, and colon. Targets should be identified through the use of advanced synthetic lethal screens that go beyond the current screens in 2D tissue culture and may include potentially more physiologically relevant systems, such as 3D cultures, organoids, appropriate genetically modified mouse models, or patient-derived xenografts. Novel targets may be derived from applying new or substantially repurposed approaches to existing synthetic lethal platforms or from using new synthetic lethal technologies.

All proposed approaches should include consideration for:

  1. Mutant KRas allele specificity within the context of human cancers of the pancreas, lung, and/or colon;
  2. Use of well characterized and appropriately annotated screening models, which could include cell lines, organoids, or tumor models;
  3. Carefully chosen end points;  
  4. Establishing appropriately powered assays;
  5. On-target versus off-target effects;
  6. Tests for reproducibility across systems;
  7. Secondary validation screens that incorporate orthogonal assays.

Examples of individual research projects that would be considered appropriate to this FOA include but are not limited to the following:

  • Identification of synthetic lethal targets for specific KRas mutant alleles using various synthetic lethal modalities, such as RNAi, shRNA, CRISPR, TALENs, ZFNs, or small molecules;
  • Identification of synthetic lethal targets for specific KRas mutant alleles involving synthetic lethality methodology and that includes inhibition of known complementary pathways, e.g., inhibitors of cell survival, metabolic, or signaling pathways, or appropriate chemotherapeutic agents;
  • Strategies to solve the non-overlapping results from simple screens;
  • Studies to identify cell-autonomous vulnerabilities revealed by co-mutations.

Examples of individual research projects that are not appropriate for this FOA include:

  • Identification of synthetic lethal targets for mutant NRas- or HRas-dependent cancers without inclusion of allele-specific mutant KRas;
  • Identification of synthetic lethal targets for specific KRas mutant alleles in studies that only use existing 2D tissue culture systems and established platforms. Applications that rely on 2D cell culture screening will have to demonstrate how the planned work represents a significant advance on previous published approaches.
  • Cancer models without inclusion of those from the pancreas, colon, and/or lung.

Network Activities

In addition to overseeing their individual research projects, the awardees will form a network that closely interacts with the RAS Program at NCI FNLCR in Frederick, MD. The goals of the RAS Program are: (1) to better understand the role of RAS mutations in cancer to solve the challenges of treating RAS-driven cancers; and (2) to build an open model of collaboration among government, academic, and industry researchers that will energize efforts to develop RAS therapeutics. The awardees from this FOA will be an extramural spoke to the RAS Program HUB, and as such each investigator will be expected to interact and contribute to the overall mission of the network and to the goals of the RAS Program. Specifically, investigators supported by this FOA will actively exchange results across the network and with the RAS Program, and participate in cross-validation of potential targets identified by other awardees.

Section II. Award Information
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
Resubmission

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are expected to differ, reflecting the actual needs of the proposed projects. It is anticipated and encouraged, however, that most requests be in the range of $450,000 to $500,000 direct costs per year commensurate with the scope and complexity of the proposed projects. Larger budgets may be requested but no request may exceed $750,000 in direct costs per year.

Award Project Period

The total project period may not exceed 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.

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

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)
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.

Required Registrations

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.
  • 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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility
Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  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 NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows.  The NIH will accept 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.
Section IV. Application and Submission Information
1. Requesting an Application Package

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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

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:

Joanna M. Watson, Ph.D.
Division of Cancer Biology
National Cancer Institute (NCI)
Telephone: 240-276-6230
Email: watsonjo@mail.nih.gov

Page Limitations

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

Instructions for Application Submission

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

Applicants should budget for the full costs of covering expenses of an annual meeting (to be held in the Washington, DC, area). 

Applicants should also budget funds in the out years for cross-validation studies of targets identified by other investigators involved in the RAS Synthetic Lethal Network.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: The specific aims to be pursued and approach(es) to be used must be also described in brief.

Research Strategy: All applications are expected to pose an original approach to pursue the identity of targets whose inhibition would induce synthetic lethality in cancers dependent on the expression of allele-specific mutant KRas. Because the underlying reason for the lack of reproducibility across platforms and models used in previous mutant KRas synthetic lethality screens could be contextual and/or technical, it is important that applicants fully define the context of the vulnerability. As part of the Research Strategy section, applicants are requested to include the following aspects:

  1. Mutant KRas allele specificity within the context of human cancers of the pancreas, lung, or colon,
  2. Use of well characterized and appropriately annotated screening models, which could include cell lines, organoids, or tumor models,
  3. Carefully chosen end points,
  4. Careful tests for screen reproducibility,
  5. Appropriately powered assays,
  6. On-target versus off-target effects,
  7. Secondary validation screens that incorporate orthogonal assays.

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. Also, all applications are expected to include a declaration and commitment that all data generated in response to this work will be made available to members of the RAS Synthetic Lethality Network and the NCI FNLCR RAS Program team, and to the general scientific community upon request, as appropriate and consistent with achieving the goals of the program.

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.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

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.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.

6. Other Submission Requirements and Information

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review Applications that are incomplete will not be reviewed.  

Post Submission Materials

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

Section V. Application Review Information
1. Criteria

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.

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? 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 for this FOA: Does the proposed study address a specific context or technical aspect of synthetic lethality screens in mutant KRas-dependent cancers of pancreas, lung, and/or colon?

Investigator(s)    

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

Innovation

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

Specific to this FOA:  Does the proposed study acknowledge and propose methods to overcome challenges of previous synthetic lethality screens? 

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? 

Specific to this FOA: Does the study clearly take into consideration potential on-target/ off-target effects, sequence coverage, and specificity? Is the study appropriately and sufficiently powered? Does the study include well characterized and appropriately annotated cells, cell lines, and conditions that will enable the investigator to fully define the context of the vulnerability identified in the screen? Does the study propose inclusion of multiple assay endpoints and appropriate validation screens that incorporate orthogonal assays? Evaluate the proposed plan for screen reproducibility.

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?   

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

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

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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.

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

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

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

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

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

Section VI. Award Administration Information
1. Award Notices

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

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the 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 terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, 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 (HHS) 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:

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 award. Specific responsibilities and rights include:

  1. The PD(s)/PI(s) for each U01 award will have the primary authority and responsibility for the project as a whole, including defining the research objectives, conducting specific studies, analysis and interpretation of research data, and preparation of publications;
  2. Representatives of each U01 award will be expected to work with the NCI Project Scientist on the coordination of intra-program activities and the scientific integration of individual projects with the RAS Synthetic Lethality Network and the NCI FNLCR RAS Program team. These actions may involve (but will not be limited to) the participation in the appropriate coordinating meetings and/or working groups, and/or teleconferences as needed;
  3. In addition to providing standard annual progress reports (see Section VI.3. Reporting), each U01 awardee will be responsible for providing other relevant information to the NCI Project Scientist, and coordinate and cooperate with the NCI FNLCR RAS Program team and NCI Program staff;
  4. Ensuring and overseeing the sharing of results, resources, and methods with the NCI FNLCR RAS Program team and NCI Program staff, and with the scientific community after cross-validation by the RAS Synthetic Lethality Network U01 awardees as appropriate and consistent with achieving the goals of the program.

Awardees will be expected to work together to develop and implement common, uniform standard operating procedures and technical formats for depositing data into public databases.

Each U01 awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

A designated NCI Program Staff member, acting as a Project Scientist, will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

Specifically, the NCI Project Scientists will:

  1. Coordinate and facilitate the interactions among all the U01 awardees under this initiative;
  2. Work closely with investigators on Collaborative Research projects to coordinate and facilitate interactions/collaborations among the U01 awardees across the network and the RAS Program team at FNCLR to establish the protocols for the network;
  3. Serve as liaison between the Collaborative Research awardees and NCI staff members and investigators involved with the NCI FNLCR RAS Program and other NIH or NCI programs, such as the NCI Center for Bioinformatics, if appropriate, facilitating interactions and scientific integration among the U01 awardees and these programs, if appropriate, for the network;
  4. Review of all major collaborations that the awardee might propose with research groups outside the RAS Synthetic Lethality Network and advise on their appropriateness before implementation to assure consistency with the goals of this FOA;
  5. Provide technical assistance and advice to the awardees as appropriate;
  6. Assist in avoiding unwarranted duplication of effort with other NCI efforts;
  7. Monitor institutional commitments and resources to the awardees;
  8. Suggest reprogramming efforts, including options to modify projects/programs when certain objectives of this FOA are not met -- specifically, the NCI Project Scientist may recommend withholding of support, suspension, or termination of a U01 award for lack of adherence to required policies and/or procedures;
  9. Develop working groups and trans-project efforts as needed;
  10. Monitoring progress and direction of awardees and working groups as needed; and
  11. Organize and conduct regular meetings to share progress either by teleconference, videoconference, or face-to-face, as needed between the awardees of the RAS Synthetic Lethal Network.

In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. The Program Official may also have substantial programmatic involvement (as a Project Scientist) and may be the same person as Project Scientist. In that case, the individual involved will not attend peer review meetings, or will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Areas of Joint Responsibility include:

The NCI Project Scientist and the PD/PIs of the U01 awards funded under the RAS Synthetic Lethality network will be jointly responsible for the coordination of intra-program activities and the scientific integration of individual projects with other appropriate NCI consortia, if required.

Although the RAS Synthetic Lethality network will not have any separate formal governing body, these activities may involve the formation of a Coordinating Group. The primary role of a Coordinating Group would be to serve as interface between the individual RAS Synthetic Lethality network project leaders and appropriate NCI programs and to facilitate reaching consensus with regard to the integration of research efforts and cross-validation of novel targets.

The NCI Project Scientist will initiate the formation of the Coordinating Group, if needed, and will facilitate its activities. A Coordinating Group will include senior representatives of each U01 project, the NCI Project Scientist, NCI FNLCR RAS Program staff members, and other NCI staff members as appropriate. Meetings of the Coordinating Group may be virtual or by teleconference.

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, including one NIH designee, who are not involved in the study will be convened. 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 HHS regulation 45 CFR Part 16.

3. Reporting

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. 

Section VII. Agency Contacts

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

Application Submission Contacts

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
Email: commons@od.nih.gov

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: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

RAS Synthetic Lethality Network
Joanna Watson, PhD
National Cancer Institute
Telephone: 240-276-6230
Email: watsonjo@mail.nih.gov

Suzanne Forry, PhD
National Cancer Institute
Telephone: 240-276-5922
Email: forryscs@mail.nih.gov

NCI-FNLCR RAS Program

Sara S. Hook, PhD
National Cancer Institute
Telephone:  301-451-2412
Email: sara.hook@nih.gov

Peer Review Contact(s)

Referral Officer
National Cancer Institute (NCI)
Telephone: 240-276-6390
Email: ncirefof@dea.nci.nih.gov

Financial/Grants Management Contact(s)

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: Hines@mail.nih.gov

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.

Authority and Regulations

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.

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