Full Text CA-95-010

HUMAN METABOLIC STUDIES OF MODIFICATION OF DIETARY FATTY ACID INTAKE
FOR PREVENTION OF BREAST, PROSTATE, AND COLON CANCER

NIH GUIDE, Volume 24, Number 14, April 14, 1995

RFA:  CA-95-010

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  0715036 
  Nutrition/Dietetics 
  Disease Prevention+ 


National Cancer Institute

Letter of Intent Receipt Date:  May 26, 1995
Application Receipt Date:  July 12, 1995

PURPOSE

The Division of Cancer Prevention and Control, National Cancer
Institute (NCI) seeks to stimulate investigator-initiated research to
elucidate mechanisms by which modification in amount and/or type of
dietary fat/fatty acids consumed may reduce risk for human breast,
prostate, and/or colon cancers.  The goal is to clarify understanding
of the relationship between dietary fatty acids and cancer in order
to refine dietary guidance on the optimal amount and type of dietary
fat to reduce the risk of several of the most common cancers in the
United States.

HEALTHY PEOPLE 2000

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 Request
for Applications (RFA), Human Metabolic Studies of Modification of
Dietary Fatty Acid Intake for Prevention of Breast, Prostate, and
Colon Cancer, is related to the priority areas of nutrition and
cancer.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0 or Summary Report:
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, 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.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research
project grant (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant.  The total project period for an application submitted in
response to this RFA may not exceed four years.  The anticipated
award date is April 1996.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
vary also.  This RFA 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.

FUNDS AVAILABLE

Up to $1.5 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 six to eight 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.

RESEARCH OBJECTIVES

Background

In the United States, breast cancer is the most common malignancy
among women; the current lifetime risk of an American woman
developing breast cancer is approximately 11 percent.  Only lung
cancer exceeds breast cancer as a cause of cancer death in U.S.
women.  Adenocarcinoma of the prostate is the most common form of
cancer in adult males, excluding nonmelanoma skin cancer.  Prostate
carcinoma now surpasses the incidence of lung cancer and represents
the second most common cause of male cancer death.  Cancer of the
colon and rectum is the third most common cause of cancer deaths in
both women and men.

The etiologic factors responsible for the development of these three
cancers are not fully understood, but the level and type of dietary
fat consumed have been hypothesized to contribute to the development
of each.  Epidemiological investigations have yielded inconsistent
findings on possible associations.  Most ecological studies provide
evidence of a positive association between intake of both saturated
and polyunsaturated, fat and breast cancer in both pre- and
postmenopausal women.  Case-control studies suggest a weaker positive
association (primarily with saturated fat in postmenopausal women)
and cohort studies suggest either a weak positive association or no
association.  Descriptive epidemiologic studies suggest a positive
association of fat intake, particularly saturated and polyunsaturated
fat, with risk of prostate cancer.  Results from case-control and
cohort studies are less consistent, but a number of these studies
suggest a positive association with saturated or animal fat intake.
For colorectal cancer, the ecological studies also support a positive
association between fat intake and risk, but suggest that effects may
differ by age and cancer site.  There is little evidence of a
consistent association with total fat intake in case-control and
cohort studies, but greater evidence for a positive association with
saturated or animal fat.

A large body of data from experiments in laboratory rodent models of
mammary and colon carcinogenesis also suggests a role for dietary
fat.  Chemically induced mammary cancers develop earlier and in
greater incidence and number in rats fed high-fat (40 percent of
calories) diets containing primarily omega-6 polyunsaturated fatty
acids (PUFA) than in rats fed low-fat (10 percent of calories) diets.
Less highly unsaturated fats and saturated fats have less effect than
corn oil, and oils composed primarily of omega-3 PUFA have not been
shown to increase mammary carcinogenesis.  Results with colon cancer
models have not been as consistent as those with mammary cancer
models.

Possible reasons for the inconsistencies in the findings between and
among the epidemiological and animal studies are numerous and include
errors in measuring dietary intake, biased recollection of diet
history, homogeneity of dietary fat intake in case-control and cohort
studies, lack of specificity or inappropriate classification of fats,
inability to separate the effect of dietary fat from that of
calories, poor measures of net energy balance in epidemiological
studies, and failure to address the interactive effects of dietary
and nondietary factors.  Nonetheless, the available evidence has been
judged strong enough by a number of expert groups to justify
recommendations for reductions in dietary fat intake to help reduce
cancer risk; the effects of dietary modification to reduce total fat
intake on cancer incidence and mortality are under investigation in
ongoing randomized clinical trials.

In contrast to the large number of epidemiological and animal studies
of dietary fat intake and risk of breast, prostate, and colon cancer,
there has been less research on potential mechanisms by which
modification of dietary fat intake may affect cancer risk.
Additional focused mechanistic investigation should help to clarify
the potential role of modification of the amount and the type of
dietary fat consumed, together with the impact of a variety of
interrelated factors, on the prevention of human breast, prostate,
and colon cancer.

Specific Objectives

Applications for investigator-initiated research project grants (R01)
that examine mechanisms by which dietary modification of fatty acid
intake may reduce risk of human breast, prostate, and/or colon cancer
are encouraged.  Research topics responsive to this RFA include human
metabolic studies to clarify the effects of reductions in the amount
or modifications in the type of dietary fatty acids consumed on
metabolic/physiologic parameters relevant to the prevention of
breast, prostate, and/or colon cancer.  Illustrative, but not
exhaustive, examples of parameters that might be examined include:
alterations in production and circulating levels of sex steroid
hormones, metabolic activity and products of intestinal microflora,
quantity and composition of adipose tissue, membrane permeability,
prostaglandin synthesis, immune function, DNA damage and repair, and
metabolism of chemical carcinogens.  Dietary modifications to be
evaluated may include various eating patterns that lead to a
reduction in total fat intake, changes in the amounts or proportions
of specific fatty acids (e.g., saturated fatty acids, trans fatty
acids, omega-3 fatty acids), or inclusion of fat substitutes or novel
fats in the diet.  In addition, the modulating effects of interacting
factors, such as caloric intake, other dietary constituents, body
mass index, and genetic polymorphisms affecting susceptibility to
cancer, may also be considered.

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 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
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 26, 1995, a letter
of intent that includes a descriptive title of the proposed research,
the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, 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 a subsequent application, the information that it contains allows
NCI staff to estimate the potential review workload and avoid
conflict of interest in the review.

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

APPLICATION PROCEDURES

The 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, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714; and from the program administrator listed
under INQUIRIES.

The RFA label available in the PHS 398 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 RFA title and number 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 photocopies, in one package, to:

Division of Research Grants
National Institutes of Health
6701 Rockledge Drive, Room 1040 MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for courier/overnight service)

At the time of submission, two additional 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
Bethesda, MD  20892
Rockville, MD  20852 (for courier/overnight services)

Applications must be received by July 12, 1995.  If an application is
received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  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.

REVIEW CONSIDERATIONS

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 the
application is not responsive to the RFA, it will be returned to the
applicant, who may submit it for review in competition with
unsolicited applications at the next review cycle.

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, all
applications will receive a written critique and may undergo a
process in which only those applications deemed to have the highest
scientific merit will be discussed, assigned a priority score, and
receive a second level review by the appropriate national advisory
council or board.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

The initial review group will also examine the provisions for the
protection of human subjects and the safety of the research
environment, as well as conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.

AWARD CRITERIA

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

The anticipated date of award is April 1996.

INQUIRIES

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, Room 212
Bethesda, MD  20892
Telephone:  (301) 496-8573
FAX:  (301) 402-0553
Email:  PilchS@dcpcepn.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Victoria R. Price
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone (301) 496-7800  Ext. 252
FAX (301) 496-8601
Email:  PriceV@gab.nci.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.399, Cancer Control.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  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 and contract 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 routing 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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