Full Text CA-92-24
BIOLOGY AND IMMUNOLOGY OF BREAST CANCER: AN INTERDISCIPLINARY APPROACH
NIH GUIDE, Volume 21, Number 28, August 7, 1992
RFA: CA-92-24
P.T. 34
Keywords:
Cancer/Carcinogenesis
Immunology
Biomedical Research, Multidiscipl
National Cancer Institute
Letter of Intent Receipt Date: November 3, 1992
Application Receipt Date: December 1, 1992
PURPOSE
The intent of this initiative is to encourage interdisciplinary
approaches to research on the basic biology and immunobiology of breast
cancer. In a recent workshop, a number of areas were identified that
would benefit greatly from additional basic research carried out in a
multidisciplinary context. These areas include immunology, molecular
genetics, endocrinology, and cell biology of breast cancer development.
The goal of this Request for Applications (RFA) is to encourage
interactive grant applications that propose research with an
interdisciplinary approach and that address unanswered questions in the
field of breast cancer.
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,
Biology and Immunology of Breast Cancer: An Interdisciplinary
Approach, 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 from interactive groups 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. Applications from minority individuals and women
are encouraged.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) Interactive
Research Project Grant (IRPG) mechanism. Information about this
mechanism of support is available in NCI program announcement PA-92-29.
The total project period for applications submitted in response to the
present RFA may not exceed four years.
This RFA is a one-time solicitation. Generally, future unsolicited
competing renewal applications as IRPGs or individual R01s will compete
with all investigator-initiated R01 applications and be reviewed
according to the customary peer review procedures 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.
FUNDS AVAILABLE
Approximately $1,500,000 in total costs per year for four years will be
committed to fund applications that are submitted in response to this
RFA. It is anticipated that at least two IRPG awards will be made,
comprising a total of six to eight individual R01 grant awards. This
level of support is dependent on the receipt of a sufficient number of
applications of high scientific merit. The earliest start date for the
initial award will be July 1, 1993. 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
Breast cancer is diagnosed in more women per year than any other
cancer. One of the major goals of the NCI is to elucidate the
biological basis of, and the role of the immune system in, breast
cancer. The NCI-sponsored Breast Cancer Research Panel, held in
Rockville, Maryland, on April 30 - May 1, 1992, provided a forum for
the discussion of current issues and opportunities in breast cancer
research. The diverse group of investigators agreed that the breast
cancer field would benefit greatly from an interdisciplinary approach.
The breast cancer literature has been growing rapidly in so many areas
that it has become extremely difficult for an investigator to be
knowledgeable in all areas. Research conducted in a collaborative
manner will promote development of new insights into this disease
because investigators from different disciplines will be able to
exchange the most up-to-date information and contribute perspectives
and scientific approaches unique for each discipline.
The Division of Cancer Biology, Diagnosis, and Centers would like to
support basic research in, but not restricted to, the following areas:
o Immunobiology - Studies of both positive and negative effects of
immune responses on breast cancer development and progression,
molecular identification of relevant breast cancer antigens, and the
development of effective strategies for immunologically-based
prevention or treatment of breast cancer.
o Cell Biology - Studies of the organization and differentiation of
breast epithelial cells during normal development and progression to
malignancy, including studies of interactions between normal and
malignant epithelial cells and the surrounding tissue/stroma.
o Molecular Genetics - Studies of the contribution of changes in the
structure or regulation of oncogenes, tumor suppressor genes, and other
important cellular genes to the development and biologic behavior of
breast cancer.
o Endocrinology (Hormones/Growth Factors) - Studies of the roles of
soluble factors and their receptors in breast cancer development and
the response to therapy. These may include, but are not limited to,
such steroid and nonsteroid factors such as estrogen, progesterone,
insulin-like growth factor, prolactin, TGF-ALPHA and TGF-BETA.
Although many exciting findings have emerged from basic research in
these areas, additional research in an interdisciplinary setting has
the potential to provide new insights and enhance the applicability of
research findings to clinical problems. The breast cancer literature
suggests that these distinct areas of research are interrelated and
that progress in understanding breast cancer development requires an
understanding of these interrelationships.
Three specific examples may be cited from the recent literature.
First, it has been shown that the extracellular matrix (ECM)
differentially regulates tissue-specific expression of several
important genes in breast epithelial cells. This indicates the
importance of verifying, in the appropriate experimental systems,
conclusions concerning gene expression reached through studies of
isolated cells in culture. Long-established tumor cell lines may not
be appropriate models for certain kinds of studies because both the
genotypes and phenotypes of such cell lines may be different from
primary human tumor cells, and because these studies provide little
insight to events that occur during the different stages of benign and
malignant breast tumors (including early, advanced, remission, and
metastasis). Hence, a clinical investigator focused on the elucidation
of events that occur during the progression of the disease, a cell
biologist focused on the development of appropriate experimental models
for breast cancer, and a molecular biologist focused on specific gene
expression in different stages or cell types of breast cancer can
benefit each other by working closely together. Second, immune system
functions can be affected by endocrine factors. For example, there is
evidence that the susceptibility of breast cancer cell lines to lysis
by lymphokine-activated killer cells is influenced by estrogens.
Expression of the lymphokine gamma interferon also appears to be
regulated by estrogens. Other cellular components of the immune system
are profoundly affected by factors found in the breast environment such
as TGF-ALPHA, and neuroendocrine factors such as cortisol and
prolactin. This indicates that the development of an effective immune
response to breast cancer cells may be as dependent on the hormonal
milieu of the tumor and the patient's psychological status as on the
presence of suitable antigens as targets. Investigators in the field
of immunology, endocrinology, cell biology, and molecular biology can
benefit each other when conducting studies to address common questions
on the immunobiology of breast cancer. Third, malignant transformation
of breast epithelial cells leads to high levels of expression of
enzymes that can degrade the intracellular matrix, which may lead to
important changes in stromal-epithelial interactions. Enzymologists,
cell biologists, and molecular biologists will all be able to
contribute to questions concerning involvement of these enzymes in
breast cell development.
These examples are not meant to indicate special areas of research
interest, but merely to illustrate how important it may be to
incorporate findings from several fields of research to arrive at
conclusions relevant to human breast cancer. The overall goal of this
basic research in biology and immunology is to translate these findings
into practical clinical applications for early tumor detection and
diagnosis, treatment of established tumors, and, ultimately, for
prevention intervention in high risk women. However, these clinical
and prevention applications are outside the scope of this RFA.
SPECIAL REQUIREMENTS
Each IRPG must contain at least three individual R01 applications, and
address a minimum of two of the major areas of research interest listed
in the Research Objectives section of this RFA. Broader diversity of
scientific areas is preferred, and although not a requirement,
applicants are encouraged to include one or more projects in
immunology. One Principal Investigator out of the group must be
identified as the "Program Coordinator," and must be cited in all
applications on page 2 of form PHS 398. The Program Coordinators of
each funded IRPG will be invited to attend the NCI Annual Specialized
Program of Research Excellence (SPORE) meeting, a meeting primarily for
recipients of the Breast Cancer SPORE Award, to present the progress
for the whole project. The IRPG Coordinator must budget funds for the
Annual SPORE Meeting. Applicants must describe how their integrated
approach will provide a more comprehensive understanding of important
problems in breast cancer basic research.
Applicants must state clearly how they plan to collaborate.
Specifically, they need to address parameters such as sharing of
resources and reagents, the planning of the overall scope of the joint
project, and the interpretation of experimental outcome. Applicants
who already have ongoing collaborations must indicate how their
response to this RFA will augment their current collaboration. Because
the ultimate goal is to arrive at conclusions relevant to human breast
cancer, projects that limit the entire studies to long-established
tumor cell lines or animal models must justify the choice of the
systems.
Although clinical and prevention applications are outside the scope of
this RFA, 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. In such a case, a letter of agreement from
either the GCRC program director or Principal Investigator must be
included with the application.
STUDY POPULATIONS
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 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 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 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
The designated "Program Coordinator" of each prospective applicant
group is asked to submit, by November 3, 1992, a letter of intent that
includes descriptive titles of each individual investigator-initiated
proposed research project, the names, institutions, addresses, and
telephone numbers of the Principal Investigators, 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. Grace L.C. Shen
Cancer Immunology Branch
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza South, Room 634
6120 Executive Boulevard
Rockville, MD 20892-9904
Telephone: (301) 496-7815
FAX: (301) 402-1037
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 business offices and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/496-7441.
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, 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**
At the time of submission, two additional copies of the application
must also be sent to:
Referral Officer
Review Logistics Branch
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 848
5333 Westbard Avenue
Bethesda, MD 20892-9912
Applications must be received by December 1, 1992. 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 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 NIH staff for
completeness and responsiveness. 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 to this RFA will be returned to the applicant by the
NCI. Applications judged to be non-responsive to this RFA may be
submitted as a component of an unsolicited IRPG, for a traditional
research project grant (R01), or for a program project grant (P01) with
modification in accordance with either the R01 or P01 guidelines. The
application would then not be considered a response to an RFA.
If the number of applications submitted is large compared to the number
of awards to be made, the NCI may conduct a preliminary scientific peer
review (triage) to eliminate those that are clearly not competitive.
The NCI will remove 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 both 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 will be by the National Cancer Advisory Board.
Review criteria for this RFA will be:
o extent to which the proposed research addresses the goals of the RFA
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 where applicable, appropriateness of the model system chosen for the
experiments proposed and potential relevance of the model system to
human breast cancer
o demonstrated expertise in both the appropriate basic and clinical
sciences of the PI and key personnel, particularly but not exclusively
in the area of the proposed research
o demonstration of availability and access to appropriate resources
necessary to perform the research
o where applicable, availability of clinical information associated
with human samples
o adequacy of provision for the protection of human subjects and the
humane treatment of animals
o adequacy of the plans for inclusion of females and minorities
o adequacy of available facilities
The reviewers will also judge the appropriateness of the proposed
budget and duration in relation to the proposed research.
For each application that is given a priority score, the review group
will assign an adjectival descriptor that reflects the extent and
effectiveness of its collaboration(s) with other applications included
in the IRPG. This assessment will be documented in a brief
administrative note in the summary statement to assist the NCI in
making final decisions on each application in the context of the
overall IRPG.
AWARD CRITERIA
The anticipated date of award is July 1, 1993. In addition to
technical merit of the application, the NCI will consider how well the
proposed research meets the goals and objectives of the program as
described in the RFA, as well as the level of total cost requested.
Only highly-rated projects will be funded. The intention is to support
IRPGs consisting of at least three high quality projects. However, for
programmatic reasons, as few as two projects of an IRPG may be funded.
INQUIRIES
Written and telephone inquiries concerning this RFA are encouraged and
should be directed to the program director listed below. NCI program
staff welcome the opportunity to clarify any issues or questions from
potential applicants.
Direct inquiries regarding programmatic issues to:
Dr. Grace L.C. Shen
Cancer Immunology Branch
Division of Cancer Biology, Diagnosis, and Centers
National Cancer Institute
Executive Plaza South, Room 634
6120 Executive Boulevard
Rockville, MD 20892-9904
Telephone: (301) 496-7815
FAX: (301) 402-1037
Direct inquiries regarding fiscal 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. 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.
.