Subject: RFA to be added to the NIH Listserver
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 17 Jan 91 10:45 EST

Good Morning Paul,
  This is one I think I did not send over to you yesterday.  It looks
as if I may have sent one twice and failed to send this.  Please
post this to the NIH Listserver as:
      RFACA-91-06.910118
  Thanks.   Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS FOR RESEARCH PROJECT (RO1) GRANTS
 
RFA NUMBER:  CA-91-06
 
ANALYSES AND PHYSIOLOGY OF ANTICARCINOGENS IN
SOYBEANS
 
P.T. 34; K.W. 0715035, 1007009, 0745027, 0710095
 
National Cancer Institute
 
Letter of Intent Receipt Date:  March 1, 1991
Application Receipt Date:  April 29, 1991
 
1. INTRODUCTION
 
The Division of Cancer Prevention and Control, National Cancer Institute
(NCI), invites applications for grants to quantify levels of total and
individual anticarcinogens in soybeans and soy products and to study
their absorption and metabolism in humans.  Epidemiologic and animal
studies suggest soybean-rich diets may reduce cancer risk.  Experimental
work indicates soybeans contain several classes of compounds in
particularly high concentrations with demonstrated anticancer activity.
Basic research on the absorption and metabolism of these compounds in
humans and accurate analytical data on the levels of these compounds in
commonly consumed soy products is needed.  These data will help to
determine the potential impact of soybeans on cancer prevention.
 
The National Institute of Environmental Health Sciences (NIEHS) is also
interested in supporting research on the anticarcinogenic effects of
human dietary constituents, but from the standpoint of their abilities
to modify the carcinogenic effects of environmental agents.
Applications that focus in this area will be assigned according to
extant Referral Guidelines.
 
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,
"Analyses and Physiology of Anticarcinogens in Soybeans," is related to
the priority area of cancer prevention.
 
II.  BACKGROUND INFORMATION
 
Populations consuming predominantly plant-based diets, for whom legumes
frequently represent an important protein source, tend to have lower
rates of several cancers than populations that rely heavily on animal
products.  One legume, soybeans, via a variety of soy products (tofu,
miso, tempeh, soymilk, natto), is commonly consumed throughout much of
East Asia where breast and colon cancer rates are low in comparison to
Western countries.  There are epidemiologic and experimental data that
suggest soybean-rich diets reduce cancer risk although the anticancer
potential of the various soy products may differ.  Soybeans contain
several classes of compounds in particularly high concentrations with
demonstrated anticancer activity, such as isoflavones, protease
inhibitors, phytosterols, saponins, and inositol hexaphosphate.  Other
compounds with anticancer activity may also exist in soybeans.
 
Isoflavones are weak estrogens that possess antioxidant activity,
inhibit the growth of neoplastic cells in vitro and the activity of
several enzymes thought to be involved in cell regulation.  Dietary
supplementation with soybean extract containing approximately 50%
protease inhibitor suppresses experimental colon cancer, topical
application inhibits oral cancer in hamsters, and dietary
supplementation with pure protease inhibitor reduces liver cancer in
rodents.  Inositol hexaphosphate enhances natural killer cell activity,
inhibits iron-generated free radicals and lipid peroxidation, slows the
growth of fibrosarcomas in experimental animals, and suppresses
chemically-induced colon cancer in rodents.  Dietary supplementation
with B-sitosterol decreases colon cell proliferation, mitotic activity,
and the incidence and number of chemically induced colon tumors.
Saponins (from soybeans and other sources) increase natural killer cell
activity, are cytotoxic against sarcoma 37 cells in vitro and in vivo,
decrease the growth of human cervical carcinoma cells in vitro and
increase the life span of mice transplanted with leukemia cells.
 
To assess the potential impact of soybeans on cancer prevention,
research that will quantify the levels of anticarcinogens in soybeans
and soy products and study their absorption and metabolism in humans is
needed.  These data will help determine the potential impact of soybeans
on cancer prevention.
 
III.  RESEARCH GOALS AND SCOPE
 
The purpose of this Request for Applications (RFA) is to solicit
applications from qualified investigators to quantify levels of total
and individual anticarcinogens in soybeans and soy products and to study
their absorption and metabolism in humans.  For the analytical work,
only those compounds in soybeans and soy products with demonstrated
anticancer activity and that are unique to soybeans and soy products or
present at substantially high levels (relative to other foods) should be
considered for analysis.  Such components include but are not limited to
isoflavones, protease inhibitors, plant sterols, saponins, and inositol
hexaphosphate.  It is essential that the validity and reliability of all
analytical procedures used in anticarcinogen assays be established and
that all methodology include quality control procedures.  In cases where
methodology is inadequate or lacking, new methods can be developed.
Total as well as individual anticarcinogens (e.g., total isoflavones and
individual isoflavones, daidzein, genistein), should be quantified.  All
factors potentially effecting anticarcinogen levels/activity should be
considered for investigation and include, but are not limited to,
anticarcinogen:  (1) form - different forms of the same anticarcinogen,
e.g., conjugated versus unconjugated; (2) stability - effects of
storage, cooking, and other food processing techniques; (3) variation -
comparisons among different brands of similar soy products and/or among
varieties of soybeans and among different batches or lot numbers of the
same soy product.
 
For the human work, studies on the absorption and metabolism of
compounds in soybeans and soy products with demonstrated anticancer
activity are to be conducted.  When feasible, dose-response
relationships between soy product/anticarcinogen intake and
anticarcinogen levels in blood and urine, and/or feces and bile should
be conducted.  These data may help to establish an approximate level of
soy product intake necessary to elicit a biologic response.  In all
cases, the soy product or extract under study should be carefully
analyzed for levels of the compound(s) to be monitored in blood, urinei,
and other biological materials.  When available, both commonly consumed
soy products and soybean extracts or pure soybean anticarcinogens should
be studied.  Both long-term feeding studies, in which anticarcinogen
levels in subjects consuming soy products/extracts over an extended
period of time and short-term studies, in which anticarcinogen levels
for a minimal period after the consumption of a single administration of
soy products, extracts, or pure compounds are studied are appropriate
under this RFA.  Factors affecting absorption and metabolism should also
be considered for evaluation, such as diet composition and
anticarcinogen form (e.g., conjugated versus unconjugated isoflavones).
 
All applicants are required to justify the selection of
anticarcinogen(s) chosen for study.  Selection should be based on the
evidence indicating the potential for a given compound to decrease
cancer risk.  Preference will be given to those components that have the
strongest anticancer potential, are most unique to soybeans and soy
products, and/or are present in high concentrations relative to other
foods.  Applicants are required to justify the specific area of research
proposed.  Work can be conducted in one or both major categories, i.e.,
analyses and/or absorption/metabolism.  Justification should be based on
the existing gaps in our knowledge and the importance of filling those
gaps to establishing the role of soybeans/soy products and/or compounds
in soybeans/soy products in the dietary prevention of cancer.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to
include minorities and women in study populations so that
research findings can be of benefit to all persons at risk of the
disease, disorder or condition under study; special emphasis
should be placed on the need for inclusion of minorities and
women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear
compelling rationale should be provided.
 
The composition of the proposed study population must be
described in terms of gender and racial/ethnic group.  In
addition, gender and racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Section 2, A-D of the Research
Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors are urged to assess carefully the feasibility
of including the broadest possible representation of minority
groups.  However, NIH recognizes that it may not be feasible or
appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority
populations (i.e., Native Americans (including American Indians
or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics).
 
The rationale for studies on single minority population groups
should be provided.
 
For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment
of diseases, disorders or conditions, including but not limited to
clinical trials.
 
The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.
However, every effort should be made to include human tissues
from women and racial/ethnic minorities when it is important to
apply the results of the study broadly, and this should be
addressed by applicants.
 
For foreign awards, the policy on inclusion of women applies
fully; since the definition of minority differs in other
countries, the applicant must discuss the relevance of research
involving foreign population groups to the United States'
populations, including minorities.
 
If the required information is not contained within the
application, the application will be returned.
 
Peer reviewers will address specifically whether the research
plan in the application conforms to these policies.  If the
representation of women or minorities in a study design is
inadequate to answer the scientific question(s) addressed AND the
justification for the selected study population is inadequate, it
will be considered a scientific weakness or deficiency in the
study design and will be reflected in assigning the priority
score to the application.
 
All applications for clinical research submitted to NIH are
required to address these policies.  NIH funding components will
not award grants or cooperative agreements that do not comply
with these policies.
 
IV.  MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) grant-in-aid (RO1).  Applicants will be responsible for the
planning, direction, and execution of the proposed project.  Except as
otherwise stated in this RFA, awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy
Statement, DHHS Publication No. (OASH) 82-50,000, revised October 1,
1990.
 
This RFA is a one-time solicitation.  Future unsolicited competing
renewal applications will compete with all investigator-initiated
applications and be reviewed by the Division of Research Grants (DRG).
However, should the NCI determine that there is a sufficient continuing
program need, a request for renewal applications will be announced.
Only recipients of awards under this RFA will be eligible to apply.
 
Approximately $900,000 in total costs per year for 3 years will be
committed to specifically fund applications that are submitted in
response to this RFA.  It is anticipated that 3 to 4 awards will be
made.  This funding level is dependent on the receipt of a sufficient
number of applications of high scientific merit.  The total project
period for applications submitted in response to the present RFA should
not exceed 3 years.  The earliest feasible start date for the initial
awards will be December 1, 1991.  Although this program is provided for
in the financial plans of the NCI, the award of grants pursuant to this
RFA is contingent upon the availability of funds for this purpose.
 
V. SPECIAL REQUIREMENTS
 
Progress reports should be included in the applications for continuation
grants each year by the Principal Investigator.
 
VI.  ELIGIBILITY REQUIREMENTS
 
Both non-profit and for-profit organizations and institutions,
governments and their agencies, and foreign institutions are eligible to
apply.
 
VII.  REVIEW PROCEDURES AND REVIEW CRITERIA
 
Upon receipt, applications will be reviewed (initially) by the Division
of Research Grants (DRG) for completeness.  Incomplete applications will
be returned to the applicant without further consideration.  Evaluation
for responsiveness to the program requirements and criteria stated in
the RFA is an NCI program staff function.  Applications that are judged
non-responsive will be returned, but may be submitted as
investigator-initiated research grants.  Questions concerning the
responsiveness of proposed research to the RFA should be directed to
program staff.
 
In cases where the number of applications is large compared to the
number of awards to be made, the NCI may conduct a preliminary
scientific peer review to eliminate those applications that are clearly
not competitive.  The NCI will remove from competition those
applications judged to be noncompetitive for award and notify the
applicant and institutional business official.
 
Those applications judged to be both competitive and responsive will be
further evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.  The second
level of review by the National Cancer Advisory Board considers the
special needs of the Institute and the priorities of the National Cancer
Program.
 
REVIEW CRITERIA
 
The factors to be considered in evaluating the scientific
merit of each response to this RFA will be:
 
1.     Extent of relevance to which the proposed research
       addresses the overall goals and objectives of the
       RFA.
 
2.     Scientific merit of the study objective(s), design,
       and methodology including considerations of
       toxicity, safety, collection and analysis of fluids
       and/or tissues, quality assurance, and statistical
       parameters.
 
3.     Basic and clinical scientific significance
       and originality of the proposed research.
 
4.     Research experience and/or competence of the
       Principal Investigator and other key personnel to
       conduct the proposed studies.
 
5.     Adequacy of time (effort) which the Principal
       Investigator and staff would devote to conduct the
       proposed studies.
 
6.     Degree to which assurances are provided that the
       proposed project protects against adverse effects
       upon humans and the environment.
 
7.     Relevance and appropriateness of the specific
       compounds chosen for study.  Only those compounds in
       soybeans and soy products with demonstrated
       anticancer potential should be considered for study.
       Preference will be given to those compounds for
       which the evidence is strongest and that are unique
       to soybeans and soy products and/or present in high
       concentrations relative to other foods.
 
The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support of each approved
application.
 
VIII.  METHOD OF APPLYING
 
The research grant application form PHS-398 (revised 10/88) must be used
in applying for these grants.  These forms are available at most
institutional business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, Room 449,
Westwood Building, 5333 Westwood Avenue, Bethesda, MD 20892, and from
the NCI Program Director named below.
 
The RFA label available in the 10/88 revision of Application Form 398
must be affixed to the bottom of the face page.  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 and number of the RFA should be typed on line 2 of face page of
the application form.
 
Submit a signed, typewritten original of the application, including the
checklist, and four (4) signed, exact photocopies, in one package to the
DRG at the address listed below.  The photocopies must be legible and
single sided.
 
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
At time of submission, send two (2) additional copies of the application
to
 
Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892
 
Applications must be received by April 29, 1991.  If an application is
received after that date, it will be returned.  If the application
submitted in response to this RFA is substantially similar to a research
grant application already submitted to the NIH for review, but has not
yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will essentially
identical applications be reviewed by different review committees.
Therefore, an application cannot be submitted in response to this RFA
which is essentially identical to one that has already been 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.
 
IX.  LETTER OF INTENT
 
Prospective applicants are asked to submit by March 1, 1991, a letter of
intent that includes a descriptive title of the proposed research, the
name and address of the principal investigator, the names of other key
personnel, the participating institutions, and the number and title of
the RFA in response to which the application is being submitted.
Although a letter of intent is not required, is not binding, and does
not enter the review of subsequent applications, it is requested to
provide an indication of the number and scope of applications to be
reviewed.
 
The letter of intent should be sent to:
 
Mark J. Messina, Ph.D.
Program Director
National Cancer Institute
DCPC
Executive Plaza North, Room 212C
Bethesda, MD  20892
Telephone:  (301) 496-8573
 
X. INQUIRIES
 
Written or telephone inquiries concerning the objectives and scope of
this RFA are encouraged and should be directed to Mark J. Messina,
Ph.D., at the above address.  The program director welcomes the
opportunity to clarify any issues or questions from potential
applicants.
 
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 Service Act., Title IV, Section 403 (Public Law
78-410, as amended; 42 USC 284) and administered under PHS grant
policies and Federal regulations 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the Intergovernmental review requirements
of Executive Order 12732 or Health Systems Agency review.