Release Date:  April 8, 1999

PA NUMBER: PA-99-081


National Cancer Institute
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Aging 
National Institute of Environmental Sciences 


The National Cancer Institute (NCI), the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA),
and the National Institute of Environmental Sciences (NIEHS) invite
investigator-initiated research grant applications to examine a range of
fundamental biological issues considered critical for progress in defeating
prostate cancer. The purpose of this announcement is to encourage new projects
focusing on the biology that underlies the development and progression of
malignant prostatic disease.  Multidisciplinary collaborations between basic
and clinical scientists in projects ranging from exploratory basic biology
studies to disease progression in appropriate biological systems or models are

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 PA,, Biology, Development, and
Progression of Malignant Prostate Disease,  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- 512-1800), or on
the Internet at the URL:  

Applications may be submitted by foreign and domestic, 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


Support of this program will be through individual research project grants
(R01) and exploratory/developmental grants (R21). 

Beginning with the June 1, 1999 receipt date, "MODULAR GRANT APPLICATION AND
AWARD" procedures will apply to all competing individual research project
grants (R01), small grants (R03), and exploratory/developmental grants (R21)
applications requesting up to $250,000 direct cost per year (see the NIH
Guide, December 15, 1998).

APPLICATION PROCEDURES  to reflect the process which has been adopted by the
NIH.  More detailed information about modular grant applications, including a
sample budget narrative justification pages and a sample biographical sketch,
is available via the Internet at url:


In the United States, prostate cancer has become the most frequently diagnosed
neoplasm and the second leading cause of cancer mortality in men after lung
cancer (SEER Prostate Cancer Trends, 1973-95 at   Its incidence rate
has continued to increase rapidly during the past two decades especially in
men over the age of 50 years, and 184,500 new incident cases were expected to
be diagnosed in 1998.  The incidence of prostate cancer increases with
advancing age and with the present trend towards an aging population, its
impact is a major public health concern.  It is imperative therefore that we
improve our understanding of the biology that underlies the growth and
development of the normal and aging prostate as well as that which underlies
the development and progression of prostatic disease. 

Prostate cancer originates as a localized lesion that subsequently progresses
to acquire increased invasive, migratory and metastatic potentials.  Our
understanding of the underlying mechanisms that dictate prostate development,
carcinogenesis, tumor progression, and metastatic dissemination is still
rudimentary.   The biochemical and molecular mechanisms that control cellular
interaction during prostate organogenesis, morphogenesis, and functional
differentiation remain undetermined.  The differentiative and proliferative
potential of prostatic stem cells have not been defined.

The progression of prostate tumors from a localized disease probably occurs
through alterations in proliferation, cell-cell adhesion, invasion potential,
and critical interactions between the prostate cancer cells and surrounding
host cells (stroma) at both primary and metastatic sites. Unfortunately,
current methods of predicting how rapidly a given prostate cancer will acquire
metastatic attributes, and progress from an androgen-dependent to an androgen-
independent state are unreliable.  The inter- and intra-cellular signaling
pathways that govern androgen-receptor mediated gene transcription and also
modulate other signal transduction pathways remain poorly characterized, and
the specific target genes and gene products that are directly controlled by
key signaling molecules during various stages of the prostate cancer
development and progression have yet to be identified.

Tumor-host interactions, pivotal to the mechanisms of cancer cell invasion,
migration, and metastasis, are also poorly understood.  Prostate cancer often
metastasizes to the bone.  Therefore, it is important to understand prostate
cancer-skeletal interactions.  It is critical to identify the molecular and
biochemical features of bone physiology and pathophysiology that influence
interaction between the prostate tumor and bone cells, and the subsequent
characteristic osteoblastic reactions that are induced when tumor cells
metastasize to the skeleton.

To improve prevention, diagnosis, and treatment of prostate cancer, it is
crucial to focus future research on the molecular, cellular, physiological,
and pathological events that lead to uncontrolled growth and metastasis.  


Strengthening research programs of relevance to prostate cancer is an
important area of emphasis for the National Cancer Institute (NCI), the
National Institute of Diabetes, Digestive Disease and Kidney Diseases (NIDDK),
the National Institute on Aging (NIA), and the National Institute of
Environmental Sciences (NIEHS).  The National Cancer Institute established the
Prostate Cancer Progress Review Group to help sharpen the focus of prostate 
research programs.  This expert review group identified a broad range of
fundamental biological issues of relevance to prostate cancer. The Review
Group has helped the NIH define and prioritize the national research agenda
for prostate cancer by identifying unmet scientific opportunities and
providing expert opinions on how to hasten progress against the disease.  
This Program Announcement is in response to their recommendations.  The
Prostate Cancer Progress Review Group Report can be found at the following web
site: - under :What's New.

Understanding prostate cancer biology, progression and metastasis are
fundamental to improving our abilities to successfully prevent, diagnose, and
treat human prostate cancer.  Among the areas encouraged by this PA are the
analysis of the developmental, biological, and molecular genetic  aspects of
prostate disease, and the use of appropriate experimental models that mimic
the clinical characteristics of prostate cancer growth, including acquisition
of androgen-independence and the propensity to metastasize to bone.  Also of
particular interest are the  identification of novel molecular and genetic
markers associated with prostate development, carcinogenesis, tumor
progression, and metastasis; the identification of the underlying mechanisms
of racial differences in prostate cancer development and progression; the
separation  of indolent and virulent forms of disease;  improvement in
diagnosing and monitoring patients; and the potential to predict the ultimate
malignant potential of a prostate tumor while it is still in a localized
state.  Additional areas of interest include studies to identify prostate
cancer stem cells; elucidate the reciprocal interactions between the prostate
tumor and host or bone cells;  and define androgen  receptor structure,
function, and interaction with other cognate cell signaling molecules,
transcriptional regulators, and cell-cell and cell-matrix intercommunication.  
Our ultimate goal is to better understand key concepts of prostate cancer
biology, and identify means to exploit such information to prevent, diagnose,
and treat prostate cancer.

The following are examples of some of the areas of research recommended by the
NCI Prostate Cancer Progress Review Group which are viewed as areas of high
program relevance by the three participating institutes.

Prostate Development, Morphogenesis and Hyperplasia:
-  What are the biochemical and molecular events that govern prostate
development from early embryogenesis to the onset of adulthood, maturation,
aging, and death?
-  What genes are directly regulated by androgen receptors during prostate
-  What other signaling pathways regulate prostate growth, development,
differentiation, and apoptosis?
- What is the nature of the stem cell for each of the prostate cell lineages? 
What are the steps in prostate-specific lineage specification, and what are
the cellular signaling events that dictate this specification?

Epithelial Cell-Stroma Interactions in the Developing, Normal, and Malignant
- What are the specific cell-cell interactions between and among developing
epithelial cells,stromal cells, endothelial cells, neuroepithelial cells, and
immune (myeloid and lymphoid) cells?
- What are the regulatory effector molecules that control reciprocal
interactions between epithelial and stromal cells, clonal interactions between
cancer epithelial cells, and the interactions between cancer cells, and
specific and non-specific cells of the immune system?

Steroid Receptor Action and Metabolism:
- What are the potential roles of nuclear receptors, their interactive
proteins, and ligand-metabolizing enzymes on prostate growth, tissue
interactions, and development?
- How do cells survive in the prostate gland upon androgen withdrawal? 
- What are the molecular and cellular mechanisms that control the response of
prostate cancer cells to alterations in androgens?
- What is the mechanism by which androgen antagonists, such as flutamide,
switch from inhibitors to enhancers of prostate cancer cell growth during
systemic therapy? 

Novel Features in Prostate Cancer:  DNA Damage/Repair or Cell Cycle:
- Are there features of DNA damage, DNA repair, or cell cycle progression that
are novel in prostate cancer cells?

Cancer Progression: Tumor Angiogenesis, Invasion, and Metastasis: 
- What are the critical housekeeping and regulatory genes that may be
associated with human prostate cancer development and progression?
- What are the biological features of indolent and virulent prostate cancer? 
- Are there molecular determinants that cause progression from high grade
prostatic intraepithelial neoplasia (PIN) to the malignant and metastatic
- Are there hereditary markers, angiogenesis switches, and/or biochemical and
molecular determinants that predict progression?  What are the molecular and
cellular mechanisms that control cell signaling and its subsequent influence
on cell motility, migration, angoigenesis and metastatic profiles?
- What are the genetic and epigenetic determinants that affect progression of
prostate cancer fromthe localized to disseminated state? What molecular
markers are associated with suchp rogression?
- What are the molecular determinants that govern cancer invasion, migration,
and metastasis? 
- What characteristics of the tumor cells are responsible for the special
affinity for bone and promote bone colonization?  Can interactions between
bone and prostate cancer cells be interrupted?
- Can additional models be developed to specifically study cancer metastasis,
particularly with respect to skeletal pathophysiology and its associated
biochemical characteristics?
- Are metastatic lesions in soft tissues (lymph nodes and lung metastases)
phenotypically different from bone metastasis?
- Can androgen-independent and metastatic phenotype be reversed?
- What is the role of immune system in prostate cancer progression?

The National Institute on Aging (NIA)

The NIA supports and conducts research on the aging process, and age-related
diseases.  This includes research focused on underlying biologic mechanisms
involved in the re-initiation of prostate growth in middle-aged men following
post-pubertal quiescence with sustained growth in older ages, and in the
relationship between this age-related growth process and the subsequent
development of prostate cancer.   Examples of research areas of interest to
NIA which are related to this announcement include a)  identification of
prostate cell types, hormones and other bioregulatory factors, with timing
processes and intracellular signaling pathways, that are involved in mid and
late life prostate growth, b) the biological , molecular, cellular and genetic
mechanisms, responsible for mid and late life prostate growth, and c) prostate
developmental processes, and/or effects of hormones and other bioregulatory
factors during development, that affects prostate growth in middle-aged and
older men. Of particular interest is research addressing the underlying causes
and biologic mechanisms responsible for racial/ethnic differences in
prevalence of prostate cancer, particularly the increased prevalence in
African American.

The National Institute of Environmental Health Sciences (NIEHS)

The NIEHS  mission includes the support of  research investigating the effects
of chemical,physical and biological environmental agents on human health and
well-being.  A significant number of human diseases come about as a result of
interactions between genetic factors and exposure to environmental factors
over time associated periods of aging. The major goal of the NIEHS is to
develop knowledge that will permit the better management of risks associated
with living in an environment that includes exposures to environmental agents
that induce adverse health effects. The NIEHS is interested in receiving
investigator-initiated research grant applications to examine the role and
mechanism of action of chemical, physical or biological environmental agents
that adversely modify cellular, molecular, and/or physiological events
associated with the growth and development of the normal, aging, and
neoplastic prostate gland. In particular, studies on environmental agent
exposure(s) that may be associated with altered programs of gene expression
for mechanisms associated with the induction or progression of premalignant or
malignant prostate disease are sought.  Such studies would elucidate and
delineate intervention principles for the prevention of environmentally-
related disease as well as for protective actions by regulatory agencies.

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  policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

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 20, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994, available on the web at the following URL address:

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.

Since this PA focuses on prostate cancer, which only occurs in men, the
required inclusion of women does not apply.


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are clear and compelling scientific and ethical reasons not
to include them. This policy applies to all initial (Type 1) applications
submitted for receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL

As part of the scientific and technical merit evaluation of the research plan,
reviewers will be instructed to address: Adequacy of plans for including
children as appropriate for the scientific goals of the research, or
justification for exclusion.

Since this PA focuses on prostate cancer, which only occurs in men, the
required inclusion of children does not apply.


Applications are to be submitted on the grant application form PHS 398 (rev.
4/98).  Application kits are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources,  National Institutes of Health, 6701
Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-
mail:  The title and number of the announcement must be
typed in Section 2a on the face page of the application.  The yes box must be
marked.  For those applicants with internet access, the 398 kit may be found

Any applicant planning to submit an investigator- initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year is advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application, i.e,
as plans for the study are being developed.  Furthermore, the applicant must
obtain agreement from the IC staff that the IC will accept the application for
consideration for award.  Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute or Center who
agreed to accept assignment of the application.  This policy requires an
applicant to obtain agreement for acceptance of both any such application and
any such subsequent amendment.  Refer to the NIH Guide for Grants and
contracts, March 20, 1998 at 

The completed original application and five legible copies must be sent or
delivered to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive
Room 1040 - MSC 7710
Bethesda, MD  20892-7710
(20817 for express service)


These instructions apply to applications requesting up to $250,000 direct cost
per year.

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 
increments) and Total Costs [Modular Total Direct plus Facilities and
Administrative (F&A) 
costs] for the initial budget period.  Items 8a and 8b should be completed
indicating the Direct 
and Total Costs for the entire proposed period of support.  

4 of the PHS 398.  It is not required and will not be accepted with the

categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be 
accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See for sample pages.)  
At the top of 
the page, enter the total direct costs requested for each year.

o  Under Personnel, list key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  The total cost for a  consortium/contractual
arrangement is included in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested. 

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team.  A biographical sketch is required for
all key personnel, following the instructions below.  No more than three pages
may be used for each person.  A sample biographical sketch may be viewed at:

- Complete the educational block at the top of the form page;
- List current position(s) and then previous positions;
- List selected peer-reviewed publications, with full citations;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date. It is important to identify all exclusions
that were used in the calculation of the F&A costs for the initial budget
period and all future budget years.

Applications requesting upto $250,000 direct cost per year and not conforming
to these guidelines will be considered unresponsive to this PA and will be
returned without further review.


Upon receipt, applications will be reviewed by the Center for Scientific
Review (CSR) for completeness.  Incomplete applications will be returned to
the applicant without further consideration.  Those applications judged to be
complete  will be further evaluated for scientific and technical merit by
appropriate Study Sections in CSR in accordance with standard NIH peer review
procedures.  Following scientific-technical review, the applications will
receive a second-level review by the appropriate national advisory council.  
Review Criteria

The five criteria to be used in the evaluation of grant applications are
listed below.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score.  For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

4.  Investigator.  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional support?

Preliminary data will not be required for R21 applications.

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the 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; the provisions
for the protection of human and animal subjects; and the safety of the
research environment.


Applications will compete for available funds with all other approved
applications assigned to that IC.  The following will be considered in making
funding decisions:  Quality of the proposed project as determined by peer
review, availability of funds, and program priority.


Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 505
Rockville, MD 20852-7385
(T) (301) 496-7028
(F) (301) 402-1037

Leroy M. Nyberg, Jr., Ph.D., M.D.
Director, Urology Programs
Bldg 45, Room 6AS-13
(T) 301-594-7717
(F) 301-480-3510
Frank Bellino, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892-9205
(T  (301) 496-6402
(F) (301) 402-0010

Michael E. McClure, Ph.D.
Chief, Organs and Systems Toxicology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences, NIH
111 T.W. Alexander Drive
Courier: 79 
P.O. Box 12233, Mail Drop EC-23
Bldg. 4401, Rm. 3417
Research Triangle Park, North Carolina 27709
RTP. NC 27709
(T) (919) 541-5327
(F) (919) 541-5064

Direct inquiries regarding fiscal matters to:

Michelle Burr
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 242
Rockville, MD 20892-
(T) (301) 496-7800
(F) (301) 496-8601

Trude Hilliard 
Grants Management Specialist
Bldg 45, Room 6AN-44B
6600 Center Drive
Bethesda, MD 20892-6600
(T)  301-594-8859
(F) 301-480-3504

Bob Pike
Grants Management Office
National Institute on Aging
Gateway Building, Suite 2N212
Bethesda, MD  20892-9205
(T) (301) 496-1472
(F)  (301) 402-3672

David Mineo
Grants Management Officer
National Institute of Environmental Health Sciences
P.O. Box 12233, MD
111 T.W. Alexander Drive, East Campus
Research Triangle Park, NC 27709
(T) (919) 541-1373
(F) (919) 541-1373


This program is described in the Catalog of Federal Domestic Assistance No.
93.396, 93.866, and 93.242.  Awards are made under authorization
of Sections 301 and 405 of the Public Health Service Act, as amended ( 42 USC
241 and 284) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74 and part 92.  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 routine 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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