Full Text CA-93-037

ROLE OF THE MICROENVIRONMENT IN BREAST AND PROSTATE CANCER

NIH GUIDE, Volume 22, Number 28, August 6, 1993

RFA:  CA-93-037

P.T. 34

Keywords: 
  0715036 
  Biology, Cellular 
  Biology, Molecular 
  Hormones 


National Cancer Institute

Letter of Intent Receipt Date:  September 10, 1993
Application Receipt Date:  November 23, 1993

PURPOSE

The Cancer Biology Branch,  Division of Cancer Biology, Diagnosis and
Centers (DCBDC) at the National Cancer institute (NCI), in
collaboration with the Chemical and Physical Carcinogenesis Branch,
Division of Cancer Etiology (DCE), NCI, invites investigator-
initiated research project grant applications to elucidate the
molecular interactions among the cell populations of human breast and
prostatic cancer that contribute to malignant progression.  New and
experienced investigators in relevant fields and disciplines may
apply for funds to pursue this research.

Breast and prostate tissues have a number of characteristics in
common; e.g., steroidal sex hormones modulate the growth and
differentiation observed during normal neonatal development and at
puberty; these same hormones are implicated in the growth of
malignancies of each organ; and hormonal intervention remains a key
component of treatment of both breast and prostate cancer in
patients.  In addition, some association between the two neoplasms is
suggested by epidemiological data of an increased risk of prostate
cancer among relatives of women with breast cancer, as well as a
significant increased risk of breast cancer in families with prostate
cancer.

It is clear that effects of the steroidal hormones on the epithelium
are mediated indirectly by interactions with stroma during normal
development and differentiation in both organs.  Epithelial-stromal
interactions may also be influenced by other hormones and growth
factors.  More importantly, there is good evidence to indicate that
aberrations in epithelial-stromal interactions occur during the
course of neoplastic progression.  Stromal components that might
participate in these micro-environmental influences include
fibroblasts, endothelial cells, macrophages, the extracellular matrix
contributed by both epithelial and stromal cells, and in the case of
breast tissue, adipocytes.  Little is known of the contribution of
this mosaic of cells to the malignant process at the cellular or
molecular level.

In animal models, a number of carcinogens (naturally occurring and
synthetic) have been implicated as potential transforming agents for
breast and prostate tissues but virtually nothing is known about the
interaction of such carcinogens with stromal components in normal or
malignant breast and prostatic tissues.

The aim of this Request for Applications (RFA) is to foster
application of recent advances in molecular and cellular biology,
using appropriate model systems, to study the effects of tumor
cell-stroma interactions relevant to tumor development and
progression in human breast or prostatic tissues.  A
multidisciplinary approach involving interactions among basic and
clinical scientists is encouraged.

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 RFA,
Role of the Microenvironment in Breast and Prostate Cancer, 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 "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Research grant 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 or
local governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Support of this RFA will be by National Institutes of Health (NIH)
individual research project grants (R01).  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  The total project period for
applications submitted in response to the present RFA may not exceed
four years.  Awards will be administered under PHS grants policy as
stated in Public Health Service Grants Policy Statement, DHHS
Publication No. (OASH) 90-50,000, revised October 1, 1990.

The present RFA announcement is for a single solicitation with a
specified deadline of November 23, 1993 for receipt of applications.
The NCI anticipates making up to twelve awards for project periods of
up to four years, if meritorious proposals and funds are available.
The anticipated award date is July 1, 1994.

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 may
vary also.

FUNDS AVAILABLE

Approximately $2,000,000 in total costs per year for up to four years
will be committed to fund applications submitted in response to this
RFA.  It is anticipated that up to twelve awards will be made.  This
level of support is dependent on the receipt of a sufficient number
of applications of high scientific merit.  Although funds to support
this program are currently 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

The incidence of breast carcinoma increases with advancing age.
About 183,000 new cases and approximately 46,000 deaths due to breast
cancer are expected to occur in 1993.  It is estimated that in 1993
there will be 165,000 newly diagnosed cases and 35,000 deaths due to
prostate cancer.  Some association between the two diseases is
suggested by epidemiological data.  For example, a family history of
prostate cancer can have a significant effect on increasing breast
cancer risk.  Similarly, a significantly higher frequency of prostate
cancer has been reported in relatives of breast cancer patients than
in relatives of control groups.

Breast and prostatic carcinomas originate in epithelial cells;
however, the growth and progression of the cancer is intimately
related to its microenvironment, i.e., the stroma.  Studies on
embryological development of the mammary gland and the prostate have
indicated that hormonally-induced ductal morphogenesis and epithelial
growth is mediated by the interactions between stroma and epithelia.
During this neonatal development the carefully timed acquisition of
steroid hormone receptors by stromal cells may be responsible for
these hormonally-induced events.  Studies on the hormonal regulation
of differentiation of the mammary gland in vitro indicate that the
presence of stromal components can determine the extent and type of
functional epithelial maturation.  However, the biochemical
interactions and molecular communications underlying these events are
poorly understood.

Breast Cancer

Familial clustering of breast cancer indicates that there is a
genetic component predisposing individuals to breast cancer.
Although it is the epithelial cell which is designated as cancerous,
it has been reported that skin fibroblasts derived from breast cancer
patients may also be altered and exhibit characteristics associated
with a transformed and/or fetal phenotype.  Furthermore, these
characteristics of fibroblasts may precede the detection of breast
cancer.

Many growth factors including bFGF, aFGF and TGFa as well as
cytokines (e.g., IL-6) may be made available to epithelial cells from
the adjacent mammary stroma.  Further, recent data indicate that the
primary source of the epithelial mitogen IGF is the breast stroma.
Analysis of fibroblasts from benign breast showed the production of
IGF-I mRNA while fibroblasts from malignant lesions expressed IGF-II
mRNA, suggesting a correlation with disease progression.

In the mammary tissue, fibroblast stroma has been shown to produce
extracellular matrix molecules such as fibronectin and tenascin that
influence cell adhesion and proliferation.  Tenascin is known to
reduce epithelial cell adhesiveness.  It is absent in normal breast,
its distribution being restricted to embryonic and malignant tissues.
A new gene coding for the enzyme stromelysin-3 (ST-3), has been
identified, that is expressed specifically in stromal cells
surrounding invasive breast carcinomas.  ST-3 is a new member of the
family of metalloproteinase enzymes which degrades the extracellular
matrix.  ST-3 is postulated to play an important role in progression
of epithelial malignancies.

Prostate Cancer

Androgens regulate the early growth and morphogenesis of the
prostatic epithelium indirectly by their effects on mesenchymal
(stromal) tissues.  Androgens may also induce the production of
andromedins from stromal cells that influence prostatic epithelial
growth by paracrine mechanisms.  One major family of growth factors
for prostatic epithelial cells may be the fibroblast growth factor
(FGF).  FGF-7, or keratinocyte growth factor, produced by the stromal
cells, in the androgen-dependent Dunning rat tumor is a mitogen for
those tumor cells that have FGF-7 receptors.  In the more malignant
androgen-independent tumors both FGF production and the tumor FGF
receptor phenotype are modified.  Androgen-sensitive LNCaP prostatic
tumor cells will form tumors in nude mice only when the inoculum is
mixed with bone- or prostate-derived fibroblasts.  Other fibroblasts
are not permissive for tumor growth.

Differences in prostate tumor incidence in different mouse strains or
in rat models may also result from characteristics of the stromal
compartment.  Recent observations indicate that mesenchymal or
stromal inductors can impose strong control over the growth of
transformed epithelial cells.

Rationale for this RFA

This RFA is intended to encourage a variety of investigator-initiated
research projects to use appropriate model systems that take into
consideration the highly interactive environment of the tumor cells,
as well as the contributions of the tumor and host cells to the
growth and metastatic spread of breast or prostatic carcinomas.  It
is also important to delineate the genetic and environmental factors
involved in stromal-epithelial interactions which are relevant to
malignant progression of hormonally regulated tumors.  It may include
collaborations among basic and clinical scientists and should embrace
an array of molecular and cellular approaches.  Evidence of the
establishment of reliable tumor cell systems or relevant tumor models
should be included in the application.

Applications that propose to explore interactions of the stroma with
only normal epithelium will not be considered responsive to this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must 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 must 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 must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398 in
the Research Plan, parts 1-4, AND summarized in part 5, Human
Subjects.  Applicants 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 is defined as 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 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 exempt from this requirement.
However, every effort should be made to include human tissues from
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
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 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 10, 1993, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NCI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Suresh Mohla at the address
listed under INQUIRIES.

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 and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892-9912,
telephone 301/710-0267.

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 number and title, "Role of the
Microenvironment in Breast and Prostate Cancer," 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 four signed, exact, clear, single-sided
photocopies, in one package with the appendices to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892-9912**

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

Referral Officer
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636A
Bethesda, MD  20892

Applications must be received by November 23, 1993.  If an
application is received after that date, it will be returned to the
applicant.  The Division of Research Grants (DRG) 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 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by DRG staff for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Complete applications will
be evaluated by NCI program staff to determine if they are responsive
to the program requirements and criteria stated in this RFA.  If the
application is not responsive to the RFA, NCI staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may receive a preliminary scientific peer review
(triage) by an NCI peer review group on the basis of relative
competitiveness.  The NIH will withdraw from further competition
those applications judged to be non- competitive for award and notify
the applicant Principal Investigator and institutional official.

Those applications judged to be responsive and competitive 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 for evaluating the scientific merit of this RFA will
be:

o  extent to which the proposed research addresses the goals of the
RFA

o  scientific and technical significance and originality of proposed
research

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research, and potential
relevance of the model system to human breast or prostate cancer

o  qualifications and research experience of the Principal
Investigator and staff

o  demonstration of availability and access to appropriate resources
necessary to perform the research

o  adequacy of provision for the protection of human subjects and the
humane treatment of animals

o  adequacy of the plans for inclusion of minorities

o  adequacy of available facilities

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

AWARD CRITERIA

The anticipated date of award is July 1, 1994.  In addition to the
technical merit of the application, NCI will consider how well the
proposed research meets the goals and objectives of the program as
described in the RFA.  Only highly-rated projects will be funded.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope
of this RFA or inquiries about whether or not specific proposed
research would be responsive are strongly encouraged and may be
directed to program staff listed below.  NCI program staff welcome
the opportunity to clarify any issues or questions from potential
applicants.

Direct inquiries regarding programmatic issues, address the letter of
intent to, and send two copies of the PHS 398 to:

Dr. Suresh Mohla
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza North, Room 505
6130 Executive Boulevard
Rockville, MD  20892
Telephone:  (301) 496-7028
FAX:  (301) 402-1037

Direct inquiries regarding fiscal and administrative matters to:

Mr. Robert Hawkins
Grants Management Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800 ext. 13

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.396, Cancer Biology.  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

.

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