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) 435-0714, 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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