Full Text CA-94-018


NIH GUIDE, Volume 23, Number 22, June 10, 1994

RFA:  CA-94-018

P.T. 34

  Disease Prevention+ 

National Cancer Institute

Letter of Intent Receipt Date:  July 25, 1994
Application Receipt Date:  November 18, 1994


The Division of Cancer Prevention and Control and the Division of
Cancer Etiology, National Cancer Institute (NCI), invite Program
Project Grants for multidisciplinary nutrition and basic biology
research relevant to the prevention of cancer.  Specifically, they
seek to encourage application of the techniques of molecular biology
and molecular genetics to address questions about the fundamental
role of nutrition in the initiation, promotion, progression, and
prevention of cancer and the use of that knowledge to develop dietary
interventions for the prevention of cancer, with a special emphasis
on breast cancer, prostate cancer, and cancer in women and

This Request for Applications (RFA) focuses on understanding the
roles of dietary patterns, individual dietary constituents, food
preparation techniques, and nutritional status in the development and
prevention of cancer.  The objectives of this RFA for Program Project
Grants are to increase the pool of quality applications addressing
nutrition and human cancer prevention using multidisciplinary
approaches; to stimulate the use of modern biological approaches and
techniques to elucidate the effects of nutrition on cancer
initiation, promotion, progression, and prevention; and to promote
the translation of knowledge of the impact of nutrition on the basic
biology of cancer into dietary interventions for its prevention.

Application of the tools and techniques of the basic biological
sciences in research designed to increase understanding of the
complex role of nutrition in cancer prevention will be enhanced
significantly by a mechanism that promotes collaborations across
disciplines and across institutions.  Therefore, investigators are
encouraged to submit Program Project Grant (P01) applications for a
multidisciplinary research program with a focused theme and a minimum
of three interrelated and synergistic individual component projects
that comprise basic research efforts and at least one component
project involving human subjects or human tissues.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Program Projects in Nutrition and Basic Biology Research for Cancer
Prevention, is related to the priority areas of cancer and nutrition.
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report:  Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary
Report: Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325
(telephone 202-783-3238).


Domestic non-profit and for-profit organizations and institutions,
public and private, are eligible to apply.  Applications may be
submitted from a single institution or may include arrangements with
multiple institutions if appropriate.  Applications from or involving
minority institutions and from minority and women investigators are
encouraged.  Foreign institutions are not eligible.


This RFA will use the National Institutes of Health (NIH) Program
Project Grant (P01).  Applicants will be responsible for the
planning, direction, and execution of the proposed projects.  The
total project period for an application submitted in response to this
RFA must not exceed four years.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the amount of the direct
cost awards will vary from $700,000 to $1,000,000.

This is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all
investigator-initiated applications and be reviewed according to the
customary peer review procedures.


Up to $4 million in total costs per year for up to four years will be
committed specifically to fund applications that are submitted in
response to this RFA.  It is anticipated that three to four awards
will be made.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NCI,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.


A.  Background

Associations of dietary patterns and constituents with mortality and
incidence have been suggested for a variety of cancers, including
breast, prostate, lung, colon, stomach, esophagus, and cervix.  Among
these, breast and prostate cancer are of particular significance
because of the large numbers of persons affected in the United
States.  The state of current knowledge of the role of nutrition, in
terms of the effects of dietary patterns, types and levels of
individual dietary constituents, and nutritional status, on the
development and prevention of breast, prostate, and other cancers is
still rudimentary.  It has been subject to the inherent
methodological limitations and inadequacies of the epidemiologic
studies and animal models upon which it is largely based.
Nonetheless, the available evidence has been sufficient to permit the
provision of general dietary guidance that may help reduce risk of
cancer and to justify the conduct of clinical trials to test the
efficacy of dietary modification or supplementation with nutrients in
the primary and secondary prevention of various cancers.

Further significant advances in understanding the role of nutrition
in cancer prevention require answers to questions about the
fundamental mechanism(s) of action of dietary patterns and dietary
constituents in the initiation, promotion, progression, and
prevention of cancer, in the context of nutrient-gene-environmental
interactions.  Information is needed regarding nutrient and dietary
non-nutrient microconstituent interactions with and effects on
cellular metabolism, genomic stability, intracellular signal
transduction, the net expression of growth-promoting and
growth-inhibiting genes, and other modulators of gene expression and
carcinogenesis.  More information is also needed about the transport
of nutrients to target tissues and about individual variability in
susceptibility and response to nutrient effects.  Such knowledge of
the basic mechanisms of action of dietary components in cancer
development is needed to provide informed recommendations about the
optimal range of intake of specific dietary constituents and to
refine and individualize dietary guidance for prevention of cancer.
Studies that provide the necessary information fall within the
province of bionutrition and encompass research on nutrients at the
cellular level and the metabolic and behavioral consequences of food
or nutrients in living organisms including humans.

With the increasing recognition of the invaluable contributions of
the techniques of molecular biology and molecular genetics to all
facets of biomedical research, it is appropriate that their use in
addressing important questions about nutrition and cancer prevention
be encouraged.  The potential for these new technologies to
revolutionize many aspects of the science of nutrition, by increasing
understanding of the nutrient-cell interactions that affect
transition from healthy to diseased cells and permitting more
reliable determination of the nutrient requirements for optimal
health and functional capacity, was given explicit recognition in the
trans-NIH Bionutrition Initiative.

Although bionutrition rests firmly on the foundation of the modern
biological sciences, it has been conceptualized as encompassing a
broad range of activities from basic research through translational
research to practical applications.  Accordingly, this RFA encourages
the submission of multidisciplinary research project applications in
the form of Program Project Grants (P01).  This type of award is
intended to support a broadly based multidisciplinary program that
has a well-defined central research focus or objective and may
include support for common supporting resources (cores) required for
the conduct of the component research projects.  The central research
focus of a Program Project Grant involves several disciplines or
several aspects of one discipline and may involve multiple
institutions.  The individual projects must be interrelated and
synergistic; hence, they result in a greater contribution to program
goals than if each project were pursued separately.  Individual
investigators may apply their specialized research capabilities to
basic research projects, clinical research projects, cancer
prevention and control research projects, or combinations of such
projects as they relate to the focused central theme of the overall
Program Project.

Applications are encouraged especially from investigative teams with
members trained in molecular, biological and genetic techniques and
nutritional science who have an interest in applying those techniques
and knowledge to address questions regarding nutrition and cancer
prevention.  Program Projects responsive to this RFA must comprise
basic research efforts and at least one component project involving
studies of human subjects or human tissues.  Applicants are
encouraged to structure Program Projects that are no larger than
necessary to achieve an effective collaborative effort among the
participating basic biology and nutrition investigators.

B.  Research Areas of Interest

The studies encouraged by this RFA will employ innovative approaches
to examine fundamental effects of nutrients and other food
constituents on initiation, promotion, progression, and prevention of
cancer, as well as individual variability in response, to develop
more effective nutrition interventions for prevention of cancer,
especially breast and prostate cancer and other cancers affecting
women and minorities.  A wide variety of potential Program Projects,
comprising individual projects ranging from basic to translational
research and practical applications, may be considered for support;
however, all applications must delineate clearly the relevance of
each proposed individual research project, especially those with a
basic biology focus, for the prevention of human cancer.

Illustrative, but not exhaustive, examples of research areas relevant
to nutrition and basic biology research for the prevention of cancer
are as follows:

o  Evaluate nutrient-genome interactions in carcinogenesis and
anticarcinogenesis, e.g., nutrient effects on DNA repair or
modulation of gene expression.

o  Examine the potential for nutrients or other dietary constituents
to influence the activation of oncogenes or inactivation of tumor
suppressor genes.

o  Study nutrient influences on differentiation and on signals
induced by physiological or chemical differentiation in various

o  Evaluate nutrient effects on growth factors for cellular
transformation, including the ability to block or prevent the
interaction of growth factors with receptors.

o  Examine nutrient-carcinogen-promoter interactions, including
cellular defense mechanisms against environmental
carcinogens/promoters that may be regulated by dietary factors.

o  Elucidate mechanisms and controls of nutrient transport to target
sites in various tissues.

o  Quantify dose-response relationships for nutrients, nutrient
derivatives, and other bioactive dietary constituents as part of the
evaluation of their absorption, metabolism, and distribution in
target tissues and their effects on molecular and cellular events.

o  Identify biomarkers indicative of early cellular transformation
that may be monitored in nutrition epidemiologic studies and
modulated in dietary intervention trials.

o  Identify biomarkers that will provide improved assessment of
dietary intake and/or nutritional status for use in nutrition
epidemiologic studies and dietary intervention trials.

o  Characterize the nature, extent, and causes of individual
variability in cancer risk and in responses to dietary constituents.

o  Develop dietary intervention strategies to modulate expression of
genetically determined cancer risk, including risk resulting from
loss of response to natural regulators of proliferation and/or risk
resulting from blocked expression of differentiation (maturation)

o  Conduct small-scale clinical/metabolic intervention studies to
test dietary modifications with potential for cancer prevention
developed on the basis of knowledge of nutrient-genomic interactions.


The Program Project Grant is intended solely for the support of a
multidisciplinary or multifaceted research program that has a focused
theme.  This unique grant mechanism builds on the leadership of the
principal investigator and the interaction of the participating
investigators to integrate the individual projects in a way that
accelerates the acquisition of knowledge beyond that expected from
the same projects conducted separately, without combined leadership
or a common theme.

A project within a Program Project is similar to the traditional
research grant application in the sense that each is reviewed for
scientific merit.  However, a component project additionally is
evaluated within the context of the special collaborative
interrelationships required for a Program Project.  In order to be
responsive to this RFA, a Program Project must include basic research
efforts and at least one component project involving studies of human
subjects or human tissues.  The relevance of each component project,
especially those projects with a basic biology focus, to the
prevention of human cancer must be clearly delineated.

A Program Project Grant may contain one or more core component(s),
each with a separate budget, for administrative or research support
services that are required for and shared solely within this
particular Program Project.  Each core must provide essential
facilities or services for two or more projects judged to have
substantial merit.  There is no allowance for unspecified
developmental research funds (seed money) in Program Project Grants.

A Program Project should include a sufficient number of
scientifically meritorious projects to promote an effective
collaborative effort among the participating investigators.  For this
RFA, Program Projects should be no larger than necessary to achieve
the desired collaboration among basic biology and nutrition
investigators.  To be eligible for an award, a Program Project must
consist of a minimum of three scientifically meritorious projects.
There is no limit for the maximum number of projects to be included
in a Program Project; however, the Program Project should not be so
large that it exceeds the scientific and administrative leadership
capability of the principal investigator, or that it loses a tight
focus.  In the peer review process, components not recommended for
further consideration are considered in the peer review evaluation of
the principal investigator's scientific judgment and program
administration skills.

The principal investigator of the Program Project Grant must be an
established scientist with a strong record of accomplishment, who is
substantially committed to and capable of exercising the
responsibility for the scientific leadership, integration and
administration of the entire Program Project.  Also, the component
projects should be directed by investigators who are experienced in
the conduct of independent research and whose backgrounds and
interests relate sufficiently to one another to allow for integrated
group pursuit of the proposed Program Project goals and objectives.



It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH-supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact persons listed below.  Program staff may
also provide additional relevant information concerning the policy.


Prospective applicants are asked to submit, by July 25, 1994 a letter
of intent that includes the names of the principal investigator and
principal collaborators; a descriptive title of the potential
application and a list of titles for the anticipated components of
the P01; identification of the organization(s) involved; and the
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, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed and to allow NCI staff to avoid conflict
of interest.

The letter of intent is to be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
Bethesda, MD  20892
Telephone:  (301) 496-3428
FAX:  (301) 402-0275


The regular research grant application form PHS 398 (rev. 9/91) is to
be used in applying for these grants.  These forms are available at
most institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, Westwood Building, Room 449, Bethesda, MD 20892; and from
the NCI program administrators named under INQUIRIES.

General instructions for the preparation of the Program Project Grant
application are contained in the application form PHS 398 (rev.
9/91).  Instructions provided in the PHS 398 application kit are
designed primarily for traditional research project (R01)
applications.  Program Project applications require additional
information and a special format as described in the publication,
"Program Project Grant of the National Cancer Institute:  Guidelines
1993."  Applicants may request a copy of this publication from the
NCI Referral Officer listed under LETTER OF INTENT.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
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 title of the RFA, "Program Projects in
Nutrition and Basic Biology Research for Cancer Prevention," and the
RFA number, CA-94-018, must be typed on line 2a of the face page of
the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact, clear, and single-sided
photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional complete copies of the
application must be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Rockville, MD  20852  (if using overnight mail services)
Bethesda, MD  20892  (if using U.S. mail)

Applications must be received by November 18, 1994.  If an
application is received after that date, it will be returned to the
applicant without review.  Also, the DRG will not accept any
application in response to this RFA that is the same as a P01
application currently being considered by any other NIH review group
or awarding unit.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not preclude
the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction
addressing the previous critique.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.


Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NCI.  Incomplete applications will be
returned to the applicant without further consideration.  If NCI
staff find that the application is not responsive to the RFA, it will
be returned 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 NCI in accordance with the review
criteria stated below.  As part of the initial merit review, a
process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications
received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.
Applications determined to be non-competitive will be withdrawn from
further consideration and the principal investigator/program director
and the official signing for the applicant organization will be
promptly notified.  The second level of review by the National Cancer
Advisory Board considers the special needs of the NCI and the
priorities of the National Cancer Program.

Peer review for scientific and technical merit of each Program
Project application submitted in response to this RFA will emphasize
two major aspects:  (1) review of the program as an integrated
research effort focused on a central theme and (2) review of the
merit of individual research projects and core components.

Review criteria for the program as an integrated effort include:

o  Scientific merit of the overall program.

o  Significance and importance of the Program Project objectives.

o  Coordination, interrelationships and synergism among the
meritorious research projects and core components as related to the
common theme of the Program Project.

o  Advantages of conducting the proposed research as a Program
Project rather than through separate research efforts.

o  Qualifications of the principal investigator to serve as both the
scientific and administrative leader of the entire Program Project.

o  Adequacy of the commitment (percent effort) of the principal
investigator to the Program Project.

o  Ability of the principal investigator to select individual
projects for both scientific excellence and relatedness to the theme
of the Program Project and actively promote interactions and

o  Presence of an organizational and administrative structure
appropriate for effective attainment of the Program Project

o  Mechanisms for internal quality control of the research.

o  Mechanisms for regular communication and coordination among

o  Institutional environment in which the research is conducted,
including the availability of space, equipment, and patients or
subjects, as well as the physical proximity of program participants.

o  Appropriateness of the size of the Program Project.

Review criteria for individual projects include:

o  Scientific merit of the individual project in the context of the
proposed program, considering the following factors:

--Specific scientific objectives of the project that benefit
significantly from, depend upon, or contribute to collaborative
interactions with other projects in the program.

--Qualifications, experience and commitment (percent effort) of the
project leader and investigators responsible for the individual
research project.

--Adequacy of the proposed means for protecting against or minimizing
potential adverse effects upon humans, animals, or the environment.

--Adequacy of adherence to guidelines for including gender and
minority representation in any study population.

--Appropriateness of the budget.

o  Intrinsic scientific merit of the proposed project.

Review criteria for core(s) include:

o  Utility of the core to the Program Project.

o  Quality of the facilities or services provided by this core
(including procedures, techniques, and criteria for prioritization).

o  Qualifications, experience, and commitment of the personnel
involved in this core.

o  Appropriateness of the budget and accountability for distribution
of costs to projects.


The anticipated date of award is July 1, 1995.

Scientific merit, as reflected by the priority score; availability of
funds; and programmatic priorities will be considered in making
awards pursuant to this RFA.


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:

Susan M. Pilch, Ph.D.
Division of Cancer Prevention and Control
National Cancer Institute
Executive Plaza North, Suite 212
Bethesda, MD  20892
Telephone:  (301) 496-8573
FAX:  (301) 402-0553

Carl E. Smith, Ph.D.
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Suite 700
Bethesda, MD  20892
Telephone:  (301) 496-5471
FAX:  (301) 496-1040

Direct inquiries regarding fiscal matters to:

Robert E. Hawkins
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800  Ext. 213
FAX:  (301) 496-8601


This program is described in the Catalog of Federal Domestic
Assistance No. 93.399, Cancer Control.  Awards will be made under the
authority of the Public Health Services Act, Title IV, Section 301
(Public Law 78-410, 42 USC 241 and Section 412, as amended by Public
Law 99-518, 42 USC 285a-1) and administered under Federal regulations
42 CFR Part 52 and PHS grant policies 45 CFR Part 74 and 92.  This
program is not subject to the intergovernmental review requirements
of Executive Order 12732 or Health Systems Agency review.

The Public Health Service strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  This is consistent with the PHS mission to protect and
advance the physical and mental health of the American people.


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