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Strategic partnering to evaluate cancer signatures.

The purpose of this initiative is to build on recent demonstrations that molecular signatures correlate with important clinical parameters in cancer. The National Cancer Institute (NCI) invites investigators to form strategic partnerships that will bring together the multi-disciplinary expertise and resources needed to determine how the information derived from comprehensive molecular analyses can be used to improve patient care and ultimately, patient outcomes. Applicants are asked to propose evaluation of potential clinical usefulness of molecular signatures already developed using a variety of molecular analysis technologies including DNA, RNA or protein-based technologies.

Molecular signatures have been able, in retrospective studies, to identify subgroups of patients whose tumors are histopathologically the same but who have different clinical outcomes. The challenge is to translate the information in these molecular signatures into tools that can be used in clinical decision-making. To meet this challenge, signatures must be confirmed in independent studies. Critical elements of signatures that correlate most strongly with the clinical endpoint of interest must be identified and confirmed. Robust assays feasible for use in the clinical setting must be developed and validated. This iterative process of signature refinement and confirmation and assay refinement requires diverse scientific expertise and access to significant patient and tissue resources.

This initiative is an open competition that will provide the cancer research community the opportunity to establish collaborations focused on the translation of promising molecular profiles toward clinical application.

NCI will continue the policy of requiring public release in a timely fashion of the rich data sets generated during these projects. Access to these data sets will benefit the entire cancer research community. This initiative will help ensure that the NCI goal of eliminating the suffering and death from cancer by 2015 is met.

The projects funded by this RFA are intended to exploit the successes of the many research projects applying comprehensive molecular analysis in cancer. Comprehensive molecular technologies have been demonstrated to provide a snapshot of the biological state of a tumor. The ability of molecular profiles to provide useful clinical information is now being demonstrated in many projects throughout the cancer research community and needs to be evaluated further. Projects are discovering molecular signatures by analysis of gene expression at the RNA level, gene expression following protein translation, gene mutations, DNA deletions, DNA amplifications, epigenetic changes of DNA and post-translational modification of proteins. The challenge is to move beyond the initial discovery of potentially useful profiles, to decide what subset of the elements in the profiles needs to be measured, to confirm that the profiles are robust and can be reproducibly measured and to evaluate the clinical utility of the profiles.

This RFA is open to all interested, qualified investigators. The initiative is intended to support projects carrying out the extensive research needed to bridge the gap between discovery of molecular profiles and their integration into clinical decision-making. Applicants should propose projects that address clinical issues or needs in a specific cancer or a closely related set of cancers or in a group of patients whose cancers have related molecular alterations. Collaborations must be established to provide all of the expertise and clinical resources required to achieve proposed project goals. It is anticipated that these will be multi-institutional projects involving investigators with expertise in technology development and application, cancer biology, oncology, pathology, clinical cancer research, biostatistics, bioinformatics and, possibly, biomedical imaging.

Applicants must propose projects that build on previously identified molecular profiles. Applications proposing only profile discovery or technology development projects will not be considered responsive to this RFA. The proposed studies should be designed to confirm and refine signatures that have been demonstrated to provide information that is potentially useful clinically and that may be used to aid in making clinical decisions. Applicants may propose to define critical components in the signature, to confirm that the selected components continue to provide the desired clinical information and to develop robust assays for measuring those components. They may continue to develop and/or modify analytical technologies and algorithms for data analysis required to meet the goals of the proposed projects.

Applicants must establish the collaborations necessary to bring together the expertise needed for the project. Successful completion of the project will require expertise in analytical technologies, cancer biology, oncology, pathology, clinical cancer research, biostatistics, bioinformatics and possibly biomedical imaging.

Applicants must describe the clinical question(s) or need(s) they plan to address. The clinical questions posed should address a well-defined clinical need in one or a closely related set of tumors or in a group of patients whose cancers have related molecular alterations. Examples of questions of interest may include, but are not limited to: risk of progression in early stage disease; prognosis at the time of diagnosis; identification of subsets within a tumor stage or grade where there is known heterogeneity in clinical behavior including differential response to standard therapies and/or radiation response; and selection of appropriate patients for or prediction of response to selected or targeted therapies. Applicants to this initiative should not propose projects addressing early detection of cancer in asymptomatic or high-risk populations or risk of progression of pre-malignant lesions.

Applicants may propose the use of a variety of analytical platforms(s). Applicants may propose to evaluate signatures the have previously been identified using analytical technologies such as, but not limited to, gene expression microarrays, SAGE, multiplex PCR or any of a large number of protein analysis technologies. Genomic analysis technologies such as array CGH, comprehensive mutational analysis technologies, SNP analysis and analysis of epigenetic events are also appropriate. Applicants must demonstrate that they have experience with the analytical technologies that will be used in the project and demonstrate that the technologies can be used for analysis of standard pathological specimens. Applicants are encouraged, but not required, to propose the use of multiple analytical strategies. For example, projects may be proposed to analyze gene expression in both frozen tissue and paraffin-embedded tissue, to analyze gene expression at both the RNA and protein level or to analyze both epigenetic alterations and gene expression. The integration of data to build clinically useful profiles that can be measured reproducibly in a clinical setting must be the focus of the project, no matter which technologies or analytic platforms are proposed.

Applicants must justify the numbers of specimens to be analyzed based on appropriate statistical designs for the proposed studies. Applicants must have established collaborations to ensure availability of the clinical materials required. The availability of tissue resources with appropriate clinical annotation is critical to the successful completion of the projects. Experience has demonstrated that the dimensionality of the molecular profiling data requires the analysis of hundreds, not tens, of specimens to get statistically significant results. Applicants may propose to obtain tissues from a previous collection or prospectively, as long as the specific aims proposed can be accomplished within the period of the grant award. Demonstrated access to the requisite tissues will be critical to the successful review of the application. It is recognized that tissue needs may change as the projects are carried out. NCI staff will work with investigators to help identify additional tissue resources needed to meet project goals.

Applicants should request sufficient resources to ensure that they will be able to collect, manage and analyze the data generated. Applicants must address issues related to obtaining, managing and controlling the quality of the clinical data needed for specimen annotation. Continued development of strategies to more effectively address issues of data management and analysis will be an inter-project cooperative activity of the funded projects.

Applicants should request sufficient resources for their bioinformatics staff to be able to provide an appropriate interface with the NCI Center for Bioinformatics (NCICB). Sharing of the data between projects where appropriate and public release of data after publication will be a requirement for this initiative. Gene expression data will be shared through the NCICB Gene Expression Database using the Gene Expression Data Portal and database. Proteomics data and other types of data can be shared through the NCICB site as the capabilities of the site are expanded. They may also be shared through investigators' websites or on other publicly available websites.

The confirmation, refinement and evaluation of clinically useful molecular profiles and the development of robust clinical assays are the primary goals of this initiative. Clinical utility of the signatures and performance of the clinical assays in the context of their intended clinical use must be validated before they can be integrated into clinical practice. Final validation of the profiles in a clinical trial setting is beyond the scope of this initiative. However, it is anticipated that some of the projects may be ready to move profiles into clinical trials as early as the midpoint of the project period. NCI staff will facilitate collaborations between the projects funded on this initiative and other clinical resources and clinical trials activities supported by NCI including: the clinical cooperative groups; the Program for the Assessment of Clinical Cancer Tests (PACCT); the SPORE programs and the NCI Cancer Centers.

This RFA will use the Natiional Institutes of Health (NIH) cooperative agreement (U01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. The anticipated award date is 1 April 2005. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application.

This RFA uses just-in-time concepts. It also uses the non-modular budgeting formats. Follow the instructions for non-modular budget research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/ policy/nihgps_2001/part_i_1.htm.

The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award." At this time, it is not known if this RFA will be reissued.

In order to ensure maximum progress in the projects funded by this initiative and to maximize progress toward the NCI 2015 goals, several special activities will be required of the funded investigators. An annual meeting of all funded investigators will be held to share progress and research insights that may benefit all of the projects.

The annual scientific meeting will be initiated after the first year of funding. One or more other focused meetings will be held each year to address arising issues or to take advantage of special scientific opportunities. Applicants should request travel funds in their budgets for key personnel to attend two meetings per year.

The funded investigators will be asked to work together on issues common to all funded projects. Although each applicant will propose an independent project, all applicants are expected to face many of the same challenges and will benefit from the experiences of and interactions with the other funded investigators. The interactions of the funded groups will be overseen by a Steering Committee made up of two investigators, the PI and one additional investigator, from each funded project and appropriate NCI staff members. A Steering Committee organizing meeting will be held shortly after funding is initiated. The Steering Committee will focus on common problems and issues, especially issues of data management and analysis. Applicants should state in their applications their commitment to participating on the Steering Committee and in interactions among the funded groups.

When proposed studies involve collection of human samples, specimens and/or clinical data, investigators should consider the issues raised and guidance provided in the NIH Brochure entitled "Research on Human Specimens: Are You Conducting Research Using Human Subjects?" (http://www-cdp.ims.nci.nib.gov/policy.html) and in the OHRP Guidance on Repositories, Tissue Storage Activities and Data Banks (http://ohrp. osophs.dhhs.gov/g-topicstest.htm) to ensure appropriate protection of human subjects in research,

Applicants must describe how they intend to meet the NIH policies for sharing of data or why data sharing is not possible. In this regard, attention is drawn to the NIH Final Statement on Sharing Research Data (http://grants.nih.gov/ grams/policy/data_sharing/index.htm and http:// grants.nih.gov/grants/guide/notice-files/ NOT-OD-03-032.html), which was published in the NIH Guide on 26 February 2003 ("Data Sharing Guidelines"). This is an extension of NIH policy on sharing research resources, and reaffirms NIH support for the concept of data sharing. The new policy becomes effective with the 1 October 2003 receipt date for applications or proposals to NIH. Investigators submitting an NIH application will be required to include a plan for data sharing or to state why data sharing is not possible. The statement required by this section should be prepared with reference to the provision below for Awardee Rights and Responsibilities within Terms and Conditions of Award.

Intellectual property (IP) issues continue to provide challenges to the establishment of complex, collaborative projects. This issue is being addressed and managed in different ways by many different projects supported by NCI. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. NIH recognizes that certain research activities may result in inventions and that grantees are entitled to protect such inventions through patenting and licensing activities in accordance with the Bayh-Dole Act, 35 USC [section] 200 et seq. and the implementing regulations, 37 CFR Part 401 ("Bayh-Dole Act"). To address the interest in assuring that research resources are accessible, NCI requires applicants who respond to this RFA to submit a plan (1) for sharing the unique research resources generated through the grant; and (2) addressing how they will exercise IP rights, should any be generated through this grant, while making such research resources available to the broader scientific community. The sharing of research resources and IP plans must make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/ nihgps_2001/) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://ott.od.nih.gov/ NewPages/RTguide_final.html and http:// ott.od.nih.gov/NewPages/64FR72090.pdf) ("NIH Research Tools Guidelines"). These documents also define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison webpage (http://www.iedison.gov/).

If applicant investigators plan to collaborate with third parties, the research tools sharing plan must explain how such collaborations will not restrict their ability to share research materials produced with NIH funding. All applicants will be expected to have addressed IP issues with their proposed collaborators before submitting their applications and to have documented the status of their arrangements by providing a copy of a signed agreement, a signed Memorandum of Understanding between collaborating institutions or a letter of collaboration countersigned by all relevant parties that describes the IP issues and provides applicants with all rights necessary to perform activities required by the research plans. Successful applicants are expected to have resolved any outstanding IP issues before funding is awarded. It is anticipated that successful applicants may subcontract with third party for profit institutions to perform certain aspects of the research plans described in their applications. Successful applicants will be expected to ensure that they obtain sufficient rights in such subcontracts to enable them to meet their obligations under the NIH Research Tools Guidelines and the Data Sharing Guidelines, both of which are extensions of the distribution of unique research resources policy contained in the NIH Grants Policy Statement (page 11-62). In drafting these subcontracts, grantees will want to give some thought to the relative rights and responsibilities of the parties, particularly with respect to the dissemination and use of raw data, results and analyses.

The NCI Technology Transfer Branch staff works with NCI funded investigators on IP issues and has developed strategies for sharing IP. Staff of the NCI Technology Transfer Branch will provide their expertise as needed to the investigators funded under this initiative and their technology transfer and grants and contracts administration offices. Addressing IP issues will be a component of the review of the projects.

As discussed earlier, grantees will be required to publicly release data to the cancer research community through the NCI Center for Bioinformatics web site or through other appropriate public websites. Applicants should commit to the public release of data and request funds in their budgets to support bioinformatics staff interactions with the NCICB staff.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants. nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714, e-mail: GrantsInfo@nih.gov.

Using the RFA label: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may nor reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/ labels.pdf.

Applications hand-delivered by individuals in the NCI will no longer be accepted. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) See http://grants.nih.gov/ grants/guide/notice-files/NOT-CA-02-002.html for more information. This policy is similar to and consistent with the policy for applications addressed to the Center for Scientific Review (CSR) as published in the NIH Guide Notice at http://grants.nih.gov/grants/guide/ notice-files/NOT-OD-02-012.html.

The CSR will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Letters of intent must be received by 22 June 2004. Applications are due 22 July 2004. The earliest anticipated start date is 1 April 2005.

Contact: James W. Jacobson, Division of Cancer Treatment and Diagnosis, NCI, 6130 Executive Blvd, EPN Rm 6035A, Bethesda, MD 20892-0001 USA, 301-402-4185, fax: 301-402-7819, e-mail: jacobsoj@mail.nih.gov; Tracy Lugo, Division of Cancer Treatment and Diagnosis, NCI, 6130 Executive Blvd, EPN Rm 6035A, Bethesda, MD 20892 USA, 301-496-1591, fax: 301-402-7819, e-mail: lugot@ mail.nih.gov.

Reference: RFA No. RFA-CA-04-015
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Title Annotation:Fellowships, Grants, & Awards
Publication:Environmental Health Perspectives
Date:May 15, 2004
Words:3310
Previous Article:Pharmacogenetics research network and knowledge base.
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