and Human Services
9000 Rockville Pike
Bethesda, Maryland 20892
PLANNING GRANT FOR COLLABORATIONS ON NUTRITIONAL MODULATION OF GENETIC PATHWAYS
LEADING TO CANCER
Release Date: September 20, 2000
RFA: CA-01-015
National Cancer Institute
Letter of Intent Receipt Date: December 8, 2000
Application Receipt Date: February 14, 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.
Return to NIH Guide Main Index
|
|
Department of Health and Human Services |
|
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |