Subject: NIH GUIDE - RFA CA-91-30 - V20(33) 09/06/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Mon, 09 Sep 91 10:07 EST

Hi Paul,
This is #8 of 11 RFAs of 910906 NIH Guide.
Please post it to the NIH Listserver as:
RFACA-91-30.910906
   Thanks, M. G. Broaddus
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA CA9130 CA-91-30 P1O1 *****************************************
 
REQUEST FOR APPLICATIONS
 
RFA:  CA-91-30
 
UNDERSTANDING THE MECHANISMS OF HORMONAL CARCINOGENESIS
 
P.T. 34; K.W. 0715035, 0760025, 0785140
 
National Cancer Institute
 
Letter of Intent Receipt Date:  October 1, 1991
Application Receipt Date:  December 12, 1991
 
I. PURPOSE
 
The Chemical and Physical Carcinogenesis Branch, Division of Cancer
Etiology (DCE), National Cancer Institute (NCI), invites
investigator-initiated research grant applications (R01s) to elucidate
the basic, complex mechanisms of hormonal carcinogenesis.  New and
experienced investigators in relevant fields and disciplines may apply
for research funds to study the basic mechanisms of steroid hormones,
particularly sex hormones, in the etiology of cancer.  This area of
research is in need of an enhanced level of interaction among
endocrinologists, toxicologists, pharmacologists, biochemists, organic
chemists, epidemiologists, pathologists, and cell and molecular
biologists.  Projects are encouraged on mechanisms of hormonal
carcinogenesis in experimental animal systems, in vitro and in vivo, and
in human tissues in vitro.
 
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), Understanding the Mechanisms of Hormonal
Carcinogenesis, is related to the priority area of 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.
 
Applications must be prepared and submitted in accordance with the aims
and requirements described in the following sections.
 
II.  ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit, public and private organizations, such as universities,
colleges, hospitals, laboratories, units of state and local governments,
and eligible agencies of the Federal Government.  Applications from
minority individuals and women are encouraged.
 
III.  MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) grant-in-aid (R01).  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) 90-50,000, revised October 1,
1990.
 
This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete with all other
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 competitive
continuation applications will be announced.  Only recipients of awards
under this RFA will be eligible to apply.
 
$1,500,000 per year for five years will be committed to specifically
fund applications submitted in response to this RFA.  It is anticipated
that seven to ten awards will be made.  This funding level is dependent
upon the receipt of a sufficient number of applications of high
scientific merit.  The total project period for applications submitted
in response to this RFA may not exceed five years.  The earliest
feasible start date for the initial awards will be July 1, 1992.
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.
 
IV.  BACKGROUND INFORMATION
 
Hormonal carcinogenesis encompasses the study of benign and malignant
tumor development in endocrine organs and target tissues by endogenously
produced or exogenously administered natural and synthetic hormones,
growth factors and other peptide and protein factors.  The field also
involves the study of agonist and antagonist agents which when
administered elicit or contribute to tumor formation.  Studies on
hormonal carcinogenesis involve the role of hormonal agents in all
aspects of neoplastic development, i.e., initiation, promotion and
progression.  A number of comprehensive reviews on hormonal
carcinogenesis are available (1-6).  Sex hormones have been
etiologically implicated in carcinogenesis for more than half a century.
Many mammalian species, including primates, develop tumors after timely
exposure to these hormonal agents, particularly estrogens.  In humans,
causality with use of these agents has been shown with endometrial,
vaginal, cervical, liver and possibly breast cancer (7,8).  In
experimental models, sex hormones used individually or in combination
have yielded high tumor incidence at a variety of organ sites, including
kidney, prostate, uterus, pituitary, mammary gland and testis (2,9,10).
From these examples, it is clear that hormones can play a fundamental
role in the initiation and promotion of cancer.  The characteristics of
hormonal carcinogenesis are:  (1) tissue and species specificity; (2)
requirements for sustained and prolonged hormone exposure at high
levels; (3) long induction period; (4) cell proliferation and
progression; (5) possible metabolic activation to reactive
intermediates; and (6) initial hormone dependency of developed tumors
that then invariably become autonomous.  Because of the evident
complexity of these phenomena, numerous disciplines and approaches may
be necessary to elucidate how exposure to normal and abnormal levels of
hormonal agents for prolonged periods affects normal cellular processes
that lead to neoplastic transformation.  Therefore, the objective of
this RFA is to encourage applications from individual investigators, as
well as collaborative efforts, from a wide range of scientists.
 
Despite increasing interest and intensity of research in the field of
hormonal carcinogenesis, little is known about the underlying
biochemical and molecular mechanisms whereby hormonally induced
neoplastic events are elicited.  Fundamental questions still persist
concerning the role of sex hormones in neoplastic transformation.  There
is a general consensus that the hormonal agents act as tumor promoters;
this is based on both epidemiological and animal data in hormone- and
carcinogen-induced neoplasms.  Tumor promotion by hormones is likely
accomplished by virtue of their biological activities affecting cell
proliferation and differentiation.  On the other hand, carcinogenic and
cocarcinogenic roles for hormonal agents still remain elusive and
controversial.  Additionally, it is not known whether epigenetic or
genotoxic mechanisms are primarily responsible for the initiation of
target tissues which eventually lead cells to hormonally induced
neoplastic development.
 
In an attempt to better define the state of knowledge and future needs
in the field of hormonal carcinogenesis, a workshop was sponsored by the
Chemical and Physical Carcinogenesis Branch, Division of Cancer
Etiology, National Cancer Institute, on September 28-29, 1989.  Workshop
speakers and participants were challenged to bear in mind several basic
questions regarding the field as different workshop topics were
discussed.  Does the hormone itself or a metabolite interact directly
with the genetic system to bring about mutation, translocation, or gene
reiterations?  How much of the hormone's role is dependent upon its
interaction with and utilization of a specific receptor mechanism?
Under conditions of a hormonally-induced malignant state, are there
changes in any oncogenes and consequently in responses such as growth
factors and their receptors, or are associated responses amplifying
these factors?  Since the development of malignancy is increasingly
thought to involve a multistep genetic response, it is possible that
hormones work cooperatively with other agents to cause cancer.  If so,
how can we better define systems to test for the role of hormones as
tumor promoters and agents in the progressive growth of malignant cells?
What is the role of hormones in the balance between normal cell growth
and terminal differentiation?  Moreover, how is this balance deranged
during the conversion of responsive cells to a malignant phenotype?
Further, how can we devise test systems to zero in on such fundamental
processes?  What genes are involved?  Since suppressor genes are
emerging as potential factors in neoplastic transformation, how can we
test for them as targets of hormonal carcinogenesis?  Can new systems be
devised which will identify suppressor genes as playing a role in the
growth and differentiation of hormonally responsive cells?  Do hormones
act as genotoxic or nongenotoxic carcinogens?
 
Workshop participants concluded that increased emphasis is necessary in
several major areas of research in order to elucidate the mechanisms of
hormonal carcinogenesis:  (1) There is a need to perform chromosomal
analysis, protooncogene and suppressor gene expression and activation
studies of the preneoplastic and neoplastic cells which arise out of
existing experimental hormonally-induced tumor models.  (2) There is a
need to develop systems in which one can readily go from the intact
animal to the in vitro environment of tissue culture.  Such systems
would facilitate the elucidation of a hormone's role in tumor initiation
and promotion as well as provide an increased understanding of the
growth regulatory mechanisms in normal and tumor cells.  (3)
Hormonally-induced expression and production of various growth factors
and their receptors in premalignant and primary neoplastic cells, and
their stromal components, needs to be assessed in order to determine the
dependencies of these changes.  (4) New approaches and new technologies
must be developed for proper analysis of several different aspects of
hormonal carcinogenesis.  For example, better systems must be devised to
establish the role of hormones as direct or indirect carcinogens.  (5)
Finally, improved systems must be developed for genetic dissection of
the problem of hormonal carcinogenesis, such as transgenic animals and
cell systems possessing genetically-altered expression and dependencies
on growth factors and their receptors.  A workshop report has been
published summarizing the meeting and recommendations for future
research (6).  This RFA seeks to stimulate new inquiries into the areas
recommended above by focusing on mechanisms of action of hormonal
agents, particularly sex hormones.
 
V. RESEARCH GOALS AND SCOPE
 
The goals of this initiative are two-fold:  (1) to elucidate basic
mechanisms of steroid hormone action that relate to the possible roles
of hormones, particularly sex hormones, as carcinogens; and (2) to
provide a means to enhance multidisciplinary investigations, including
consortial arrangements.  This area of research is in need of an
enhanced level of interaction among endocrinologists, toxicologists,
pharmacologists, biochemists, organic chemists, epidemiologists,
pathologists, and cell and molecular biologists.  Projects are
encouraged on mechanisms of hormonal carcinogenesis in experimental
animal systems, in vitro and in vivo, and in human tissues in vitro.
Research to be funded under this RFA includes, but is not limited to,
studies on:  (1) the hormonal metabolites that could lead specifically
to genetic damage or chromosomal malfunction, i.e., chromosomal
fragmentation, non-disjunction, altered repair processes, or shifts in
DNA methylation states; (2) karyotypic, cytogenetic and morphologic
changes in models of hormonal carcinogenesis; (3) the role of androgens,
anabolic agents and progestins in hormonal carcinogenesis in organ sites
such as the liver and mammary gland; (4) establishment of new in vitro
experimental models for studying hormonal carcinogenesis in various
understudied organ sites such as pituitary, testis and uterus; (5) the
role of specific hormones in the oncogenic process through the use of
transgenic animals or gene transfected cells; and (6) molecular
mechanisms of hormonally induced carcinogenesis, e.g., DNA base sequence
changes, genetic or epigenetic mechanisms.
 
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 and
compelling rationale should be provided.
 
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  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 are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, the
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 the NIH are required
to address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.
 
VI.  REVIEW PROCEDURES AND CRITERIA
 
A. REVIEW PROCEDURE
 
Upon receipt, applications will initially be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the applicant
without further consideration.  Evaluation for responsiveness to the RFA
is an NCI program staff function.  Applications will be judged to
determine if they meet the goals and objectives of the program as
described in the RFA.  Applications judged non-responsive will be
returned to the Principal Investigator but may be submitted as
investigator-initiated research grants at the next receipt date.
Questions concerning the relevance of proposed research to the RFA are
to be directed to the Program Director as described in INQUIRIES
 
If 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 withdraw from further competition those applications judged to be
noncompetitive 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.
 
B. REVIEW CRITERIA
 
Applications responsive to this competitive solicitation will be
reviewed in accordance with the criteria stated below:
 
o scientific merit, feasibility, and originality of the proposed
research;
 
o technical adequacy and sufficiency of scientific methodology proposed
to reach research objectives;
 
o research experience, competence, commitment, and time availability of
the Principal Investigator and proposed staff and/or collaborators to
perform the proposed studies;
 
o documentation of the adequacy of existing/proposed facilities,
equipment, and resources of all laboratories involved in the research
efforts, e.g., patient populations, specimens (This consideration will
include laboratory safety, biohazard, and animal welfare practices and
procedures.); and
 
o appropriateness of requested budget relative to the work proposed and
appropriateness of the timetable for completion.
 
The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each approved
application.
 
VII.  METHOD OF APPLYING
 
The most recent revision of the research grant application form PHS 398
(revised 10/88) must be used in applying for these grants.  The
application package is available at most institutional business offices;
from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, 5333
Westbard Avenue, Bethesda, MD 20892 telephone (301) 496-7441; and from
the NCI Program Director named below.
 
The RFA label available in the 10/88 revision of application form PHS
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
RFA number and title must be typed on line 2 of the face page of the
application form.
 
Submit a signed, typewritten original of the application, including the
Checklist, and four signed, exact photocopies, in one package to the DRG
at the address below.  The photocopies must be clear and single sided.
 
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
**The mailing address given for sending applications to the Division of
Research Grants is the ZIP code address for the National Institutes of
Health.  Applicants who use express mail or a courier service are
advised to follow the carrier's requirements for showing a street
address.  The address of the Westwood Building is:  5333 Westbard
Avenue, Bethesda, MD 20816.
 
At time of submission, two additional copies of the application must be
sent to:
 
REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892
 
If the applicant has an approved assurance covering the research
(multiple project assurance for animal subjects), the applicant must
provide with the application certification of Institutional Review Group
(IRG) approval if humans are involved, and verification of the
Institutional Animal Care and Use Committee (IACUC) approval if animals
are involved.  These reviews and approvals must occur prior to
submission of the application for award and the certifications and
verifications must be submitted with the application.  Failure to
provide required certifications and verifications within the application
could result in deferral or rejection.  If animals or humans will be
subjects of the research at performance sites other than the applicant
organization, the applicant must identify, within the application, the
assurance status of each participant.  Failure to provide this
information within the application may result in deferral or rejection.
 
Applications must be received by close of business December 12, 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 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
that is essentially identical to one that has already been reviewed.
This does not preclude the submission f substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
VIII.  LETTER OF INTENT
 
Prospective applicants are asked to submit by October 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 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.
 
The letter of intent is to be sent to:
 
Dr. Lea I. Sekely
Carcinogenesis Mechanisms
Chemical and Physical Carcinogenesis Branch
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Suite 700
Bethesda, MD  20892
Telephone:  (301) 496-5471
FAX:  (301) 496-1040
 
The mailing address given is the ZIP code address for the National
Institutes of Health.  Applicants who use express mail or a courier
service are advised to follow the carrier's requirements for showing a
street address.  The address of Executive Plaza North is:  6130
Executive Boulevard, Rockville, MD 20852.
 
IX.  INQUIRIES
 
Written and telephone inquiries concerning the objectives and scope of
this RFA, and inquiries about whether or not specific proposed research
would be responsive, are encouraged and are to be directed to Dr. Lea I.
Sekely at the above address.  The Program Director welcomes the
opportunity to clarify any issues or questions from potential
applicants.
 
Written or telephone inquiries of a budgetary, administrative, and/or
policy nature should be directed to:
 
Ms. Sara Stone
Grants Management Team Leader
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 66
FAX:  (301) 496-8601
 
X. AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic Assistance
No. 93.393, Cancer Cause and Prevention Research.  Awards are made under
the 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.
 
REFERENCES
 
1.  Rivera, E.M., Bern, H.A. Hormones and cancer.  In:  A. Vernadakis,
and P.S. Timeras (eds.), Hormones in Development and Aging, pp.
645-672.  Jamaica (NY):  Spectrum Publications, Inc., 1982.
 
2.  Li, J.J., Nandi, S. Hormones and carcinogenesis:  laboratory
studies.  In:  K.L. Becker (ed.), Principles and Practice of
Endocrinology and Metabolism, pp.  1643-1647.  Philadelphia:  J.B.
Lippincott Co., 1990.
 
3.  McLachlan, J.A. (ed.), Estrogens in the Environment II:  Influences
on Development.  New York:  Elsevier Science Publishers, 1985.
 
4.  Liehr, J.G., DaGue, B.B., Ballatore, A.M., and Sirbasku, D.A.
Multiple roles of estrogen in estrogen-dependent renal clear cell
carcinoma of Syrian hamster.  In:  G.H. Sato, A.B. Pardee, and D.A.
Sirbasku (eds.), Growth of Cells in Hormonally Defined Media, Vol. 9,
Book A, pp.  445-458.  Cold Spring Harbor Conferences on Cell
Proliferation.  New York:  Cold Spring Harbor Press, 1982.
 
5.  Li, J.J., Nandi, S., and Li, S.A. (eds.), Hormonal Carcinogenesis.
New York:  Springer Verlag, 1991.
 
6.  Li, J.J., Mueller, G.C., and Sekely, L.I. Meeting report:  current
perspectives and future trends in hormonal carcinogenesis.  Cancer Res.,
51:  3626-3629, 1991.
 
7.  Invasive cervical cancer and combined oral contraceptives.  WHO
collaborative study of neoplasia and steroid contraceptives.  Br. Med.
J. (Clin.  Res.), 290(6473):  961-965, 1985.
 
8.  Henderson, B.E., Ross, R.K., Pike, M.C. and Casagrande, J.T.
Endogenous hormones as a major factor in human cancer.  Cancer Res., 40:
3232-3239, 1982.  9.  Li, J.J., and Li, S.A. Estrogen carcinogenesis in
hamster tissues:  a critical review.  Endoc.  Revs., No. 4, 11:
524-530, 1990.
 
10.  Drago, J.R. The induction of Nb rat prostatic carcinomas.
Anticancer Res., 4:  255-256, 1984.