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

Cancer Target Discovery and Development (CTDD) Network (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of RFA-CA-11-010

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-CA-12-006

Companion Funding Opportunity

None

Number of Applications

Up to two applications per institution that does not have any CTDD award resulting from prior RFA-CA-11-010. Only one application is allowed if an institution already has a CTDD U01 award as defined in Section III. 3. Additional Information on Eligibility.

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

93.393, 93.394, 93.395, 93.396

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) and the Cancer Target Discovery and Development (CTDD) initiative is to promote innovative research on high throughput approaches to the discovery and characterization of new cancer targets and their modulators. Projects resulting from this FOA are expected to bridge the gap between the enormous volumes of data generated by the comprehensive molecular characterizations of many cancer subtypes and the ability to use these data for the development of human cancer therapeutics and associated response markers. Applicants must propose research projects focused on high-throughput identification and/or characterization of potential targets for cancer therapy, and/or the identification of small molecules that modulate validated cancer targets. Proposed projects are expected to combine in-depth mining of large-scale genomic data, systems biology analyses and/or experimental approaches to provide initial characterization of functional significance. This characterization may involve the studies of modulation/perturbation of the potential targets (or target combinations) using, e.g., small molecules and/or oligonucleotides. Development and/or improvement of technologies serving the main goals of the project may also be proposed. In addition to conducting individual research projects, the CTDD awardees will also be expected to contribute to trans-Network activities, including participation in joint pilot research projects.  Successful applicants will join the existing Network.

NOTE on Pre-Application Meeting: The NCI will hold a public pre-application teleconference for investigators planning to submit applications in response to this FOA on April 24, 2012 from 2:30 p.m. EST. Additional details on this teleconference are found on ocg.cancer.gov web site. Participation in the meeting, although encouraged, is optional and not required for application submission.

Key Dates
Posted Date

March 30, 2012

Open Date (Earliest Submission Date)

May 21, 2012

Letter of Intent Due Date

May 21, 2012

Application Due Date(s)

June 21, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

October-November 2012

Advisory Council Review

January 2013

Earliest Start Date(s)

April 1, 2013

Expiration Date

June 22, 2012

Due Dates for E.O. 12372

Not Applicable.

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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.

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

PURPOSE

This Funding Opportunity Announcement (FOA) is designed to support research projects focused on the identification, initial characterization, and early development of novel targets for cancer treatment as well as probes affecting those targets.  The overarching goal of the Cancer Target Discovery and Development (CTDD) Initiative and the subject of this FOA is to bridge the gap between the enormous volumes of data generated by the comprehensive molecular characterizations projects of a number of cancer types and the ability to use this knowledge for the development of human cancer therapeutics and response prediction.

Research projects to be proposed in response to this FOA must be based on the utilization of the comprehensive characterization datasets for the cancer types generated by programs such as The Cancer Genome Atlas (TCGA, http://cancergenome.nih.gov/), Therapeutically Applicable Research to Generate Effective Treatments (TARGET, http://target.cancer.gov/), and related programs. The approaches are expected to be comprehensive (i.e., genome-wide in scope). Where appropriate, bioinformatics should be combined with high throughput assays in experiments designed to demonstrate that affecting potential targets can lead to the desirable outcomes such as the abrogation of the cancerous phenotype, decreased metastatic potential, and/or selective eradication of cancer cells. Bioinformatics may also drive the development of probes that specifically affect the function of the prospective targets and other experimental approaches relevant to their characterization. The functional agents (e.g., small molecules or oligonucleotides) may be developed and investigated either as phenotype perturbagens for target characterization/validation and/or as prototypes for therapeutics.

This FOA builds upon the lessons learned in the pilot initiative "Cancer Target Discovery and Development". All investigators with appropriate expertise and capabilities are encouraged to consider the opportunity with the exception of the investigators funded under the RFA-CA-11-010 (CTDD, http://ocg.cancer.gov/programs/CTDD.asp). .

BACKGROUND

Various large-scale programs are generating comprehensive molecular characterizations of a various cancer types. These characterizations are based on a reasonably large number of patient cases with the same diagnosis for which robust clinical data are available. Consequently, the characterizations provide enough power to detect molecular alterations occurring at 5-10% frequency. The common goal of these ongoing activities is to provide to the scientific community a compendium of nucleic acid changes present in each tumor type. The currently available compendia of alterations in adult and pediatric cancers are products of such initiatives as TCGA (http://cancergenome.nih.gov/), TARGET (http://www.target.cancer.gov/), Cancer Genome Characterization Initiative (CGCI, http://cgap.nci.nih.gov/cgci.html), International Cancer Genome Consortium (ICGC, http://www.icgc.org/), and other projects. The catalogs include the characterizations of the cancers’ genomes (including mutation profiles), transcriptomes and epigenomes by a variety of approaches and techniques that also vary in resolution. For instance, those that are based on nucleic acid sequencing allow for the definition of the cancer-specific changes at the level of a single nucleotide, whereas the resolution of nucleotide array-based techniques may be limited to 1-10 kb.

Regardless of how the changes are defined, when properly validated and analyzed the diverse catalogue of raw information has the capacity to lead to the discovery of potentially critical cancer-driving functional changes. The molecular compendia are available to the scientific community through databases with the appropriate protections to ensure patient confidentiality and privacy. Programs such as TCGA, TARGET, CGCI, ICGC, and other projects are expected to generate publicly available datasets for up to 5-10 cancer types per year for the next 3-4 years. The web sites associated with each project provide the real-time availability of the molecular characterization data.

It is widely appreciated that the molecular characterizations of cancer abnormalities provide information that is essential but not sufficient for thorough understanding of the disease in terms of prognosis, diagnosis, responsiveness to therapies, and, most importantly for this FOA, identification of optimal therapeutic targets. The lack of complete understanding is due in part to the limited knowledge of gene activities within cells and organisms (on several levels of complexity). Even in a healthy person/state the functions of many genes remain unknown. The various aberrations that occur in cancer cells can affect gene activities and other cellular processes but these interactions and pathways are largely unknown.

Moreover, growing evidence points to the importance of yet another understudied component of the cancer phenotype; the heterogeneous, polyclonal nature of tumors. It is not clear how differences in cellular composition (stroma, adjacent tissue, endothelium, various clones of transformed cells, etc.) affect the patients’ responses to specific treatments. In addition, the alterations underlying specific cancer types need to be interpreted within the complex networks of interactions that occur in various differentiation states of the cell type of origin and the genetic background of the individual which may have diverse consequences. Therefore, to translate the compendia of molecular data into insights about cancers that will be applicable in the clinic, new approaches are needed that would combine broad bioinformatic analyses, comprehensive experimental characterizations and probing of cancer-defining molecular interdependencies using high throughput methodologies, and systems biology tools.

The rapidly increasing availability of comprehensive molecular characterization data inspires and facilitates the efforts to gain the understanding of fundamental attributes of individual cancer types in terms of initiation, progression, metastasis, and, most importantly, their potential vulnerabilities that may be exploited in humans in the therapeutic context. The challenge is to develop and substantiate appropriate tools for such investigations. Whereas conventional biochemical and molecular biology approaches are important for an in-depth understanding of specific, individual alterations, these approaches are not practical (in that they are too time consuming and costly) for global characterizations of the multiple, complex cancer-specific alterations and their functional interdependencies. Therefore, novel approaches are needed that would combine comprehensive bioinformatic analyses of the available data in the context of systems biology to unravel the complexity of key regulatory functions in specific cancer types. Further insights into such functions and their corroboration need also to be gained through existing as well as improved high-throughput experimental approaches.

Multivariate bioinformatic analyses have the potential to identify some of the dysregulated pathways within cancer cells harboring a specific set of molecular alterations and predict the interactions across the key pathways that characterize cancer phenotype(s). Modeling and simulation of these interactions may aid the identification of a set of pathways that are critical because of their roles in, e.g., tumor formation and/or progression. To realize the potential further methodological and technical improvements are needed. Particularly important would be the integration of analytical and modeling approaches with experimental phenotypic modulations and probing of cancer-specific molecular interdependencies. To optimize the use of such integrated approaches, dedicated efforts are needed to generate robust and preferably standardized “discovery and corroboration pipelines” that would include appropriate quality control measures and preliminary validations performed in unsupervised or semi-automated way.

To support the testing of these novel approaches in a pilot program, the NCI established the Cancer Target Discovery and Development (CTDD) Network.  Centers funded under this program through the American Recovery and Reinvestment Act (ARRA), conducted individual investigator-initiated projects as well as collaborated on joint projects within the Network. The CTDD pilot projects ranged from bioinformatics analyses, genome-wide loss-of-function screening, targeted gain-of-function candidate gene validations, use of mouse model-based screening, and small molecule high-throughput screens to identify pertubagens of cancer phenotypes. The progress accomplished indicates that it is possible to: a) identify targets and processes upon which cancers with defined genotypes become dependent; and b) to probe these dependencies in a systematic way in search for novel therapeutic opportunities. This progress was greatly facilitated by the comprehensive and integrated efforts of the CTDD awardees interacting as needed. Given these indications of feasibility, structured efforts towards this novel paradigm for target identification and exploitation are highly warranted.

SPECIFIC RESEARCH OBJECTIVES AND REQUIREMENTS

Main Goal. All research projects proposed in response to this FOA must address the main goal of the CTDD, i.e., the systematic identification of novel potential targets that may inspire future development of therapeutic applications. The target candidates must be identified and characterized through exploration of the genomic and other molecular alterations. This approach takes advantage of the catalogues of alterations already available for many cancer types and new datasets for additional cancer types as they are generated.

All proposed projects must be relevant to the identification and characterization of candidate targets. These projects are expected to use a combination of approaches.  Not exclusive examples are bioinformatics/systems biology and small molecules or other agents (e.g., oligonucleotides) to probe the modulation and perturbation of the function(s) of the potential targets in the cancer types examined.

A potential target that reflects dependencies of a given cancer type and may have a potential for therapeutic exploitation can include, among others, a gene or gene product, a biomolecule, a pathway. Combination of targets (e.g., multiple genes within a pathway, genes involved in synthetic lethality) are also possible and may be proposed for exploration under this FOA.

Cancer Characterization Data. All projects must be based on the utilization of the comprehensive characterization datasets for the cancer types generated by programs such as TCGA, TARGET, CGCI, ICGC and related initiatives generating similar catalogs of cancer-specific alterations.  The integration of an application's results with the data of the large scale molecular characterization projects should be an effective use of NCI supported generation of resources.  Applicants must plan for and accommodate the continued generation and availability of new (and/or expanded) datasets over the anticipated project period. Applicants have the flexibility to propose studies focused on a specific tumor type (s) for the initial period and to outline plans for study expansion on a selection of other tumor types for which data become available during the project period.

Scope of the CTDD Initiative. As general guidance for applicants how many cancer types/datasets should be explored in the proposed projects, the goal for the entire program is to build the needed capabilities and to complete the identification of potential candidate targets for all or nearly all cancer types for which adequate characterization datasets are available now and will become available within the next 3-4 years. In five years, the entire CTDD Network is expected to identify and characterize targets for approximately 25 or more (if possible) cancer types. Many of these cancer types could be analyzed in multiple ways and/or by more than one group. Therefore, it will be essential for applicants responding to this FOA to have or build the capacity for in depth analyses and experimental approaches utilizing datasets for many cancer types. A broad “coverage” is the paradigm for this initiative. Moreover, given the scope of genomic datasets to explore, it is important that the applicants address the issue of economy-of-scale, including throughput, cost efficiency, and speed.

Scope of Individual Applications. The bioinformatic approaches should be comprehensive in that they include the entire cancer genome, and/or transcriptome, and/or epigenome, in context of the available clinical data. The mining of combination of these biological data layers is highly desirable. Projects that mine all the molecular and clinical data available for a cancer may be based entirely on bioinformatic/systems biology approaches. Applications that combine bioinformatic approaches with appropriate high throughput experimental determinations are encouraged. Where appropriate, the proposed projects could include probing for the functional aspects of the putative target candidates through experimental modulations of cancerous phenotypes, development of agents to interfere with the identified potential targets, and other experimental approaches. Examples of approaches are listed below. Functional probes (e.g., small molecules or oligonucleotides) may be developed and investigated either as phenotype perturbagens for target characterization, validation, and/or as prototypes for therapeutic agents. It is desirable and optimal for the goals of this FOA if the proposed project is focused on targets that are relevant to (and will be explored in) multiple cancer types.

As long as the general goals and requirements of the CTDD Initiative are addressed, applicants may propose to design the project(s) in the way that fits best their expertise, capabilities and resources. For example, projects may be primarily oriented on novel, advanced, integrative bioinformatic analyses/mining of the large-scale data sets from several cancer types, with a limited effort on experimental characterizations/confirmations. Alternatively, a proposed project may emphasize experimental approaches, albeit with adequate bioinformatic capabilities to interpret the results and integrate them with the existing large-scale molecular characterizations.

Each application must constitute a self-standing, independent research project(s). However, each team will also have to offer some special capabilities and resources suitable for joint, trans-Network endeavors (see details below under subheading “CTDD as a Network”). In addition, the NCI recognizes that some institutions may have strong groups of investigators with broader and more comprehensive bioinformatics and/or experimental capabilities. Therefore, each institution is allowed to develop and submit up to two applications for two different projects. If desired and appropriate, these two projects may be designed as a broadly-based interactive effort.  The exception is the institutions that already have one CTDD U01 award; only one application is allowed for them (see Section II.3 of this FOA Number of Applications).

Examples of concepts and approaches that could be addressed in the application are listed below. These examples are non-exclusive and other relevant novel concepts and approaches are also encouraged.

Examples of Concepts:

Examples of Approaches:

NOTE ON PRIORITIES:

Whereas each application is expected to address both the identification and characterization of new potential targets and probes, applicants may choose to emphasize one of these aspects over the other. Applicants may also include studies aimed at methodological improvements or development of new technologies relevant to the main research goals of their projects.

Priority will be given to broad-based studies with a high potential to reveal truly novel targets and/or target combinations/cancer dependencies that are relevant to multiple cancer types. It is expected that these goals can be maximized by using high throughput approaches. These studies should allow for prioritization of the potential utility of multiple candidate (most, if possible) targets in a given category.

One desirable outcome would be to broadly expand the definition of genetic alternations that are deemed "targetable" for therapeutics.  Well-studied targets, such as kinases or phosphatases, are of limited interest except in specific, justified circumstances (such as to clarify their roles within important cancer pathways, their effects on other potential targets, and/or as components in strategies aimed at combinations of targets).

Models used in experimental studies must be well defined and well characterized. Models must have the corresponding genetic background of the cancer(s) investigated, e.g., functional single nucleotide polymorphisms (SNPs), DNA segment copy number alterations (CNAs) and/or mutations. Such models may include cell lines or xenografts from patients of specific signature subtype(s). Well justified novel mouse model systems of human cancers, e.g., for the high-risk, poor prognosis cancer subtypes generated through rapid, non-traditional approaches, may also be considered. Established cancer cell lines may be proposed but only if there is sufficient information documenting that these cell lines maintain phenotypic attributes of a given cancer and their signature of molecular abnormalities (at the genetic and other levels) matches respective cancer signatures established for biospecimens from patients.

If libraries of small molecules are used, applicants should 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 discouraged.

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 to validating results.

Applicants are strongly encouraged to plan for experimental approaches and bioinformatic solutions that would facilitate sharing data, protocols, and results across the Network. For example, research protocols must be complete, specific and detailed that it can be reproduced 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 recapitulation 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 bioinformatic protocols/workflows to be developed.

Long-term Translational Perspective and Potential. The CTDD initiative is focused on the conceptual phase of target identification and exploration up to a stage of proof-of-concept. Thus, further development of specific therapeutic approaches based on identified potential targets or small molecule pertubagens is beyond the scope of this FOA. Nevertheless, it is expected that the CTDD Program will build foundation inspiring such translational/developmental efforts in the future. Therefore, applicants are encouraged to consider how such future developments could take place and summarize very briefly their translational expectations in the application.

NON-RESPONSIVE

The following research directions/approaches are outside the scope and non-responsive to this FOA:

Use of cell lines or xenografts without adequate experimental validation that they include the relevant molecular aberrations found in human cancers investigated together with the corresponding cancer phenotypes. For example, unsuitable as biological models for this FOA may be: a) cell lines established long time ago and extensively propagated (unless detailed documentation is available that they match the attributes of human clinical cancers); or b) xenografts established through old protocols that involved a cell passage through a tissue culture stage, no matter how transient.

CTDD as a Network:

The CTDD awardees will become part of the interactive Network established in 2012 with a Steering Committee as the governing body (for details see Section VI.2. Terms and Conditions of Cooperative Agreements). The programmatic goal and priority of the CTDD initiative are to promote individual research projects that will ensure broad coverage of as many cancer types as possible as well as facilitate complementary interactions across the CTDD Network. For example, it is anticipated that more than one group may investigate a specific cancer type provided that their approaches are complementary rather than overlapping.  For cancers which are studied by a number of existing Centers, the approach needs to be unique to be justifiable.

In addition, the entire CTDD Network is expected to benefit from a range of unique bioinformatics/systems biology approaches. To optimize these benefits, diverse and complementary experimental technologies and capabilities will be required. Moreover, for productive trans-Network interactions, it is important to have teams with unique and complementary expertise and capabilities in both exploring large-scale genomic data and employing high-throughput experimental approaches and models. It is expected that the funded Network will include groups with a wide breadth of approaches and will have efficient means to disseminate expertise, data, and tools of individual groups across all awardees. Thus, to facilitate and enhance interactions among the groups, there is an expectation that the CTDD awardees will have open data and resource sharing plans to ensure rapid dissemination of relevant information. Moreover, it is also expected that final validated results will be made publicly available (through a CTDD web site maintained by the NCI, http://ctd2.nci.nih.gov/DataMatrix/CTD2_DataMatrix.html). 

The planned trans-Network interactions will include participation of each awardee in pilot, exploratory research activities. Pilot projects and other joint trans-Network activities will be reviewed by the Steering Committee and recommended for approval by the NCI. The Steering Committee will establish specific procedures guiding how pilot projects will be formulated and proposed for approval and collaborative execution. Thus, no such pilot projects are to be included in the application. Nonetheless, applicants are encouraged to indicate their unique expertise and capabilities that may be useful for such joint endeavors as well as outline general directions that, in their opinion, will particularly warrant joint exploration.  

Section II. Award Information
Funding Instrument

Cooperative Agreement:

Application Types Allowed

New

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The NCI intends to commit $6 million (total cost) in FY 2013 to fund 6-8 awards as a result of this FOA.  The number of awards is contingent upon NCI appropriations and the submission of a sufficient number of meritorious applications. It is expected that $6 million will be available in subsequent years, but the funding in years 2014-2016 and the amounts will depend on annual appropriations.

Award Budget

Budget requests are expected to range from approximately $500,000 up to $750,000 per year (direct costs) depending on actual scope and needs of the proposed project. No requests shall exceed $750,000 per year (in direct costs).

Award Project Period

A project period of up to 4 years may be requested if justified. Shorter project periods may also be requested commensurate with the nature of the project(s) proposed.

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

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

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 must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

With the exception noted below, 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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

Restriction: Note that none of PD(s)/PI(s) on applications submitted in response to this FOA may be a PD/PI on a CTDD U01 award already funded under the previous CTDD RFA-CA-11-010.

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.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application.

A single institution, defined as institution identifiable by a unique Institutional Profile Number (IPS), may submit only up to two applications provided that institution is NOT already a CTDD U01 awardee (funded as a result of the prior CTDD RFA-CA-11-010). Only one application is allowed if an institution already has a CTDD U01 award.

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, 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:

The letter of intent should be sent to:

Daniela S Gerhard, Ph.D.
Director, Office of Cancer Genomics
National Cancer Institute
Building 31, Room 10A07, MSC 2580
31 Center Drive
Bethesda, MD 20892-2580
Telephone: (301) 451-8027
FAX: (301) 480-4368
Email: gerhardd@mail.nih.gov

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory 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.

Page Limitations

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

Budget

All applications must be submitted using itemized detailed budget.

In the Budget requests, applicants must include (under Other Expenses) the cost of the anticipated future joint trans-Network activities (such as pilot projects). These funds can be activated and use only for the purposes of trans-Network activities that are properly recommended by Steering Committee and approved by the NCI. It is expected that while in year 1 trans-Network projects would be relatively small, 10-20% of the scope, in later years the trans-network research may include up to 50% of the scope if there is a scientific rationale to do so.

Applicants must also budget funds for up to 4 persons per year for travel to annual Steering Committee meeting.

Given the nature of the anticipated projects, a substantial commitment (of at least 1.2 person-months) is expected for any individual designated as the PD/PI (either as a single PD/PI or as one of multiple PD(s)/PI(s)) on the application. PD(s)/PI(s) on CTDD awards will be required to maintain commitment at least at this minimal level throughout the entire project period (see Terms and Conditions of Cooperative Agreements under Section VI.2. of this FOA.

PHS 398 Research Plan Component

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

Research Strategy (standard page limit of 12 pages applies)

Small Molecule Compound or Oligonucleotide Libraries

Translational Potential

Trans-Network Capabilities:

Protection of Human Subjects:

Applicants must thoroughly follow instructions when completing the Section "Protection of Human Subjects".

Projects proposed in response to this FOA (i.e., bioinformatic research using large datasets with associated clinical data) should be considered as “human subject research”. It is possible that some of the proposed studies will fall under "Exception 4" as defined in section 46.101(b) of 45 CFR 46.). If the proposed projects are using existing data and none of the investigators have access to subject identification, such projects are likely to not be considered human subjects research. However, it is applicants’ responsibility to determine properly the status of research proposed. Therefore, applicants are strongly encouraged to check the current regulations and consult additional resources that NIH provides, including this Frequently Asked Questions web page: http://grants.nih.gov/grants/policy/hs/faqs_aps_exempt.htm?print=yesg regarding the status of their proposed research and information/documentation that may be required.

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 modifications:

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, with the following modifications:

Provide the following additional Appendix Materials:

Foreign Institutions

Foreign (non-US) 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 in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (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 SF 424(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.

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 Central Contractor Registration (CCR). 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 and responsiveness by the NCI, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.  

Post Submission Materials

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

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.

For this particular announcement, note the following:

An U01 application under this FOA must be for a single well-developed, research project focused on the systematic identification and characterization of novel potential therapeutic targets and their pertubagens/modulators. These projects are expected to be relevant to and inspire future development of novel therapeutic strategies.

Overall Impact

Reviewers will provide an overall impact/priority 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?

In addition, specific for this FOA: How important are the proposed approaches for achieving the goals of the entire CTDD Program as defined in the FOA? How high is the potential of the proposed research in terms of prospects for future development of novel therapeutic modalities and expediting the transition of high-content molecular data through identification of targets and modulators?   

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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?  

In addition, specific for this FOA: How appropriate and how unique are expertise and capabilities of the applicant team in terms of their usefulness for joint endeavors across the CTDD Network? How is the inclusion of other collaborators addressed; such as, experts in specific cancer types that are expected to be studied?

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? 

In addition, specific for this FOA: To what degree are the proposed methods and approaches novel in terms of the ability to generate unique types of bioinformatic analyses and/or high throughput experimental data and/or creative integration of such data? 

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

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

In addition, specific for this FOA: How adequate is/will be the capacity to study datasets for multiple cancer types and plans for possible scaling up as data sets for additional cancer types become available during the project period? Are the plans for technology/methodology research and improvements sufficient to serve, facilitate, and enhance the proposed project? How well are the plans for the necessary informatics infrastructure, including data/information transfers and exchanges, developed? Are they sufficient for the anticipated needs of the proposed project and the entire CTDD program? How compelling are the proposed approaches in terms of breadth of coverage, economy of scale, throughput, cost efficiency, and speed? Is the transition potential addressed adequately?

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? 

In addition, specific for this FOA: How appropriate is the environment of the applicants' institution in terms of bioinformatics infrastructure needed for massive data processing? How valuable and unique are applicants' resources as potential components of the interactive network? If the application is for one of two interactive projects, to what degree will they benefit (and be enhanced) by mutual interactions?

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/priority score, but will not give separate scores for these items.   

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

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/priority 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  Panel conveyed by the NCI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Applications will be assigned to the NCI.   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 Cancer Advisory Board. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) 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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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 (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 PDs/PIs will have the primary responsibility for:

A PD/PI on a CTDD award will be expected to maintain significant effort commitment not smaller than that stated in the application (at least 1.2 person-month).

Awardees will be expected to work together and 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 will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

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

The NCI reserves the right to adjust funding, withhold, suspend, or terminate the support to the awardee if the team is unable to meet the performance requirements set forth in these Terms and Conditions of Award, or significantly lower the level of performance.

Additional NCI staff members may be designated to have substantial involvement. The substantially involved NCI staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NCI waivers according to the NCI procedures for management of conflict of interest.

In addition, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship and programmatic stewardship of the award, and will be named in the award notice. If this individual is substantially involved in the CTDD activities, s/he will not attend peer review meetings of renewal and /or supplemental applications or will seek NCI waiver if such participation is essential.

Areas of Joint Responsibility include:

The Steering Committee will serve as the main governing board for CTDD. The CTDD Steering Committee will consist of the following voting members:

Each voting member will have one vote. The Steering Committee will be chaired by one of the CTDD PDs/PIs on rotating basis to be determined upon start of the Program. In the absence of PD/PI, a designated senior investigator will chair Steering Committee meeting.

The Steering Committee may include additional individuals as non-voting members and may also form subcommittees as needed. Additional NIH/NCI representatives may serve as non-voting members and/or members on subcommittees as needed.

The Steering Committee will conduct one face to face meeting a year and monthly teleconferences (or more frequent meetings as needed).

The main functions of the Steering Committee will include the following:

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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually 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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Daniela S. Gerhard, Ph.D.
Director, Office of Cancer Genomics
National Cancer Institute
31 Center Dr; 10A07
Bethesda, MD 20852
Telephone: 301-451-8027
Fax: 301-480-4368
http://ocg.cancer.gov/

Peer Review Contact(s)

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service regular or express mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefof@dea.nci.nih.gov

Financial/Grants Management Contact(s)

Michael S. Zarkin
Grants Management Specialist
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, Room 243
Rockville, Md. 20892-7150 (USPS)
Rockville, Md. 20852 (express delivery)
Telephone: 301-496-2261
FAX: 301-496-8601
Email: zarkinm@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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