RFA-CA-01-015: PLANNING GRANT FOR COLLABORATIONS ON NUTRITIONAL MODULATION OF GENETIC PATHWAYS LEADING TO CANCER

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PLANNING GRANT FOR COLLABORATIONS ON NUTRITIONAL MODULATION OF GENETIC PATHWAYS LEADING TO CANCER Release Date: September 20, 2000 RFA: CA-01-015 (Reissued as RFA-CA-07-502) National Cancer Institute Letter of Intent Receipt Date: December 8, 2000 Application Receipt Date: February 14, 2001 Expiration Date: February 15, 2001 PURPOSE The National Cancer Institute (NCI) intends to develop a program for both basic and clinical research in areas related to dietary nutrients as modifiers of genetic pathways leading to cancer. This Request for Applications (RFA) invites applications for P20 planning grants that will lead to collaborative interdisciplinary research teams to resolve complex gene-nutrient interrelationships that are related to cancer prevention. The general purpose of this initiative is advance the science of nutrition by capitalizing on recent advances in molecular biology and genetics within three extraordinary opportunities identified in The National Cancer Institute’s 2001 Bypass Budget, i.e. Genes and the Environment, Defining the Signatures of Cancer Cells, and Molecular Targets. All approaches to planning are encouraged, as long as they address the following essential features: a cancer focus, institutional commitment, organizational capabilities, facilities, and interdisciplinary coordination and collaboration. A second RFA is anticipated that will invite applications for the establishment of a multi-year collaborative research project using the Cooperative Specialized Center (U54) mechanism. RESEARCH OBJECTIVES Background The impetus for this overall program comes from increasing observations that link diet with cancer risk. Data from a multitude of sources, including epidemiological and controlled preclinical experiments, indicate that several dietary components may have a role in the cancer process. While the risks of breast, prostate, colon, lung and liver cancers have been associated with dietary patterns, frequent inconsistencies are noted. These inconsistencies may reflect the multi-factorial and complex nature of cancer and/or the specificity that individual dietary constituents have in modifying genetic pathways. Defining the precise role that nutrition has in cancer prevention is complicated by the numerous and diverse essential (i.e. folate, selenium, vitamin E, n-3 fatty acids and calcium) and non-essential (i.e. oligosaccharides, allyl sulfurs, carotenoids, flavonoids, isothiocyanates) components that may alter one or more phases of the cancer process. Since variation occurs in cancer incidence among and within populations with similar dietary patterns, the absolute response may reflect complex interactions occurring among nutrients and with other extrinsic environmental factors, or with intrinsic gender, ethnic and genetic factors. Traditional reduction approaches used by some to examine gene-chemical interactions may be inadequate for the study of nutrition and cancer because of the likelihood that multiple nutrients interact with multiple genes to create a phenotypic effect. The National Cancer Institute’s 2001 Bypass Budget (http://2001.cancer.gov/opps.htm) identified six extraordinary research opportunities that are rife with possibilities for accelerating progress against cancer. Opportunities for moving nutrition research into a new era in cancer prevention are identifiable in several of these extraordinary opportunities, i.e. Genes and the Environment, Defining the Signatures of Cancer Cells, and Molecular Targets. By addressing the role that diet and dietary components have in each of these areas, better insights will emerge about who might benefit from selected dietary intervention strategies. Astonishing strides have been made in the understanding about how molecules and pathways in pre- and malignant cells differ from their normal counterparts. The discovery and exploitation of molecular targets for cancer prevention have arisen from the convergence of scientific advances in several areas but has not been totally embraced by the nutrition research community. Preclinical evidence demonstrating that several dietary components can influence Phase I and II enzymes involved with carcinogen metabolism, as well as alter pathways involved with cell proliferation and differentiation, serve as justification for expanding this area of investigation while simultaneously satisfying NCI’s goal to identify Molecular Targets of Prevention and Treatment. All cells have unique signatures that are characterized by active and inactive genes and cellular products. Evidence already exists that both essential and non-essential nutrients can influence cell cycle regulation, processes involved with replication/transcription, and factors involved with apoptosis. Part of this protection may relate to their ability to prevent oxidative damage. Compounds suppressing oxidative stress have been reported to produce changes in c-fos, c-jun, and c-myc and the tumor suppressor gene p53, as well as genes coding for the syntheses of protective molecules such as metallothioneins, glutathione, and stress proteins. Preclinical evidence exists that such diverse dietary components as folate, allyl sulfur, genistein and resveratrol can alter genes and pathways associated with tumor cell proliferation and apoptosis. This evidence raises the possibility that the expanded use of molecular signatures will assist in developing effective dietary intervention strategies. Defining interactions between genetic pathways and dietary constituents should assist in clarifying discrepancies among pre-clinical, epidemiological, and intervention studies. For example, knowledge about genetic pathways that are, and are not, influenced by carotenoids may clarify why ?-carotene intake emerged in several prospective epidemiological investigations as inversely related to lung cancer risk, while it is contraindicated in controlled trials with smokers. By simultaneously examining other extrinsic factors such as tobacco exposures and the occurrence of genetic changes accompanying pre- neoplastic lesions, it may be possible to clarify why a nutrient might be an antagonist in one situation yet an agonist in another. It is becoming increasingly apparent that resolving complex issues about intrinsic and extrinsic determinants of cancer are hampered by the limited scientific breadth of single investigators and institutions and/or access to study populations. New and exciting opportunities for addressing several overarching nutrition and cancer issues can emerge by establishing meaningful integrated, interdisciplinary collaborations among scientists at the interface between the biological domain and medical practice. Objective and Scope The explosive increase in the understanding of new genes and pathways for regulating cell growth and development, and evaluating the response to hormones and other chemicals synthesized by the body offers exciting opportunities for understanding how the diet influences cancer prevention. Large cohort studies that can define key interrelationships between genes and dietary exposures, including the content of specific nutrients in target tissues, are sometimes beyond the capabilities of individual institutions. By fostering collaborations across investigators and institutions that use new genetic approaches, the overall program seeks to improve opportunities to address critical research questions that define the mechanism by which nutrients modify the cancer process, characterize how gene variation in key molecular pathways modulate the response, and how to assess/monitor the biological response to foods and their isolated constituents. The overall program for this RFA and an anticipated second RFA is meant to foster new interdisciplinary approaches to resolving issues about the physiological significance of dietary components as regulators of genetic and epigenetic pathways involved with cancer. It is anticipated that the information gained will provide guidance for the development of dietary intervention strategies that are effective in cancer prevention. Innovative approaches are needed to address the complex problems related to diet and cancer prevention. Significant advances will require that research approaches go beyond customary thinking and organizations to the creation of new cross-disciplinary and multi-institutional collaborations. The expansion of these new functional links not only among basic, clinical, and population scientists, but also across very diverse fields of science and technology, are key to timely and comprehensive answering of questions. By fostering collaborative and integrative research approaches, this new initiative seeks to help delineate the role that diet has in cancer prevention. The following are examples of some of the areas of research that are viewed as relevant for the development of the P20 application and ultimately for establishing a collaborative interdisciplinary research program that address the role of diet in cancer prevention: 1) Use of natural genetic variations to elucidate how nutritional exposures are linked to phenotype, 2) Characterization of molecular events that govern the ability of specific nutrients to alter cell cycle checkpoints, 3) Credentialing of target receptors for cancer prevention that are modified by dietary constituents, 4) Methylation patterns that are influenced by dietary manipulations that influence gene expressions and cellular phenotypes, 5) Antioxidant scavenging and oxygen stress modulation by nutrients, 6) DNA repair mechanisms influenced by dietary constituents, 7) Signaling pathways that regulate cancer growth, development, differentiation and apoptosis as regulated by dietary components, and 8) Features of DNA damage, DNA repair or cell cycle progression that makes them particularly susceptible to dietary intervention strategies Study Design/Timetable The duration of the planning phase in response to this P20 RFA is anticipated to be no more than six months. During this phase participating scientists and resources will be identified and the overall conceptual framework defined. These actual larger collaborative projects would be invited during the anticipated phase II (U54) solicitation. Although the actual organizational structure for a collaborative project may vary depending on the specific research problem, each will need an administrative management plan. The model for the large-scale collaborative project may consist entirely of a research and administrative structure that facilitates data coordinating and information dissemination. The large-scale collaborative project may also include: (a) Pilot projects aimed at enriching approaches or techniques available to the large-scale project and/or adding investigators outside the scientific mainstream of the project and (b) Core resources to speed progress in the collaborative project or improve technologies. During Phase I participating investigators will need to identify benchmarks that could be used for assessing accomplishments in the anticipated large scale collaborative project. It is anticipated that each application will have a Principal Investigator (PI) who will chair and be assisted in governing by a multidisciplinary research team of investigators in meeting the goals of the project. The ultimate collaborative project must be developed around scientists with expertise to delineate the role that diet has in regulating genes involved with cancer. Each collaborative project must include expertise in nutrition and in genetics. These investigators may be at the same institute as the PI or at a different location. Merits of each Collaborative Project will be based on the sciences embodied to address the role of diet and genetics in cancer prevention. MECHANISM OF SUPPORT Phase I will use the National Institutes of Health (NIH) P20 Planning Grant mechanism. The P20 mechanism supports planning for new programs, expansion or modification of existing resources, or feasibility studies for new approaches. This mechanism with set-aside funds is to stimulate submission of applications that will create collaborative approaches to solving complex issues involving nutrition and genetic pathways. It is anticipated that this RFA will stimulate added interest in this research arena. This increased recognition will foster an expansion in the number and scope of investigator-initiated research projects. Ultimately this RFA will lead to an expansion of capabilities of addressing multiple research issues related to nutrition and cancer prevention. The organizational structure proposed by the applicant should foster multidisciplinary collaborations not currently existing. Applicants will be responsible for the execution of all activities supported by this grant. Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement October 1998. Budget and Related Issues. ALLOWABLE COSTS The P20 will provide support for: 1. Salaries for key personnel 2. Equipment, supplies and personnel to support an administrative structure 3. Planning and evaluation activities that may include the costs for: a. Travel and per diem for key personnel related to planning for the collaborative project b. Workshops, seminars, retreats and other forums to strengthen, stabilize and consolidate interactions and cooperation, to identify new areas of opportunity and high priorities the planning partnership evolves. Funds may NOT be used to purchase laboratory equipment or to support individual or pilot projects. FUNDS AVAILABLE The NCI intends to commit approximately $600,000 in FY 2001 to fund up to 6 awards in response to this RFA. An applicant may request a project period of up to 6 months. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and Local governments, and eligible agencies of the Federal Government. Participation by scientists within industry is also encouraged as appropriate. Foreign institutions are not eligible for this announcement. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply. Note that this is the first phase of an anticipated two phase initiative. A more extensively planned and detailed application will be expected for the anticipated Phase II (U54) solicitation. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. John A. Milner Nutritional Science Research Group Division of Cancer Prevention National Cancer Institute 6130 Executive Blvd., Room 212, MSC-7328 Rockville, Maryland 20852 Phone: (301) 496-8573 FAX: (301) 402-0553 E-mail: milnerj@mail.nih.gov Direct inquiries regarding review issues to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8329 Rockville, Maryland 20852 (Express Courier) Bethesda, Maryland 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 E-mail: tf12w@nih.gov Direct inquiries regarding fiscal matters to: Sara Stone Grants Administration Branch National Cancer Institute 6120 Executive Blvd., Room 243 Rockville, Maryland 20852 Telephone: (301) 496-7800 FAX: (301) 496-8601 E-mail: stones@gab.nci.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by December 8, 2000, a Letter of Intent that includes a descriptive title of the proposed research, name, address and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and number and title of the RFA in response to which the application may be submitted. Although a Letter of Intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows National Cancer Institute staff to estimate the potential review workload and to plan the review. The Letter of Intent is to be sent to Dr. John A. Milner at the address listed under INQUIRIES by the Letter of Intent receipt date listed. SCHEDULE Letter of Intent Receipt: December 8, 2000 Application Receipt Date: February 14, 2001 Peer Review Date: May/June 2001 Review by NCAB Advisory Board: September 2001 Earliest Anticipated Start Date: September 28, 2001 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, Maryland 20892-7910, telephone (301) 710-0267, E-mail: grantsinfo@nih.gov. For those applicants with internet access, the 398 kit may be found at http://grants.nih.gov/grants/forms.htm. The RFA label available in the PHS 398 (rev. 4/98) 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 not 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive Room 1040 - MSC-7710 Bethesda, MD 20892-7710 (20817 for express service) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8109, MSC-8329 Rockville, MD 20852 (express courier) Bethesda, MD 20892-8329 Applications must be received by February 14, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the National Cancer Institute. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the National Cancer Institute in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed assigned a priority score, and receive a second level review by the National Cancer Advisory Board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this application bring together sufficient expertise to address an important problem? If the aims of the application are achieved, how will the collaborative undertaking advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the application? Does the applicant acknowledge potential problem areas and consider alternative tactics? Do letters of commitment support the priorities and objectives of the plan for the collaborative partnership? Do officials provides confidence that these commitments will be stable and long lasting? If applicable, does the applicant provide evidence about the adequacy of the resources (e.g., discretionary resources, space, faculty positions, protected time for research). 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? The adequacy of the qualifications and experience of the collaborating investigators to provide strong programmatic (e.g., scientific) and administrative leadership. If applicable, the adequacy of the qualifications and experience of other key personnel in both to successfully plan for and achieve the objectives of this planning effort. 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? How would resource/infrastructure provide long-term stability to the activities of the partnership? What are the qualifications of key personnel associated with the resource/infrastructure. 6. Other considerations The initial review group will also examine: the appropriateness of proposed project budget and duration, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion, the provisions for the protection of human and animal subjects, and the safety of the research environment. Intellectual Property (if applicable). The adequacy of the intellectual property plan, including provision for sharing of research tools/materials, and of agents from commercial partners. AWARD CRITERIA Applications recommended by the National Cancer Advisory Board will be considered for award based upon (a) scientific and technical merit, (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood, and (c) availability of funds. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub- populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the ANIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators may also obtain copies of the policy from the program staff listed under INQUIRIES. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA, Cooperative planning Grant for Collaborations on Nutritional Modulation of Genetic Pathways Leading to Cancer, is related to priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.399. Cancer Control wards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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