MOLECULAR EPIDEMIOLOGY OF PROSTATE CARCINOGENESIS

Release Date:  January 29, 1999

PA NUMBER:  PA-99-055

P.T.

National Cancer Institute
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Environmental Health Sciences

Letter of Intent Receipt Dates:  March 18, 1999; October 20, 1999
Application Receipt Dates:  April 26, 1999; November 19, 1999

This Program Announcement (PA) replaces PA-95-084, which was published in NIH
Guide for Grants and Contracts, Vol. 24, No. 30, August 18, 1995.

PURPOSE

The National Cancer Institute (NCI), the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) and the National Institute of
Environmental Health Sciences (NIEHS) invite investigator-initiated research
grant applications of molecular epidemiologic studies for understanding
prostate cancer development and progression.  The purpose of this initiative
is to stimulate development and application of biological markers of prostate
cancer risk and tumor aggressiveness in developing strategies for prostate
cancer prevention and control.  Of special interest are studies of markers to
elucidate multiethnic differences in prostate cancer susceptibility.

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 PA, Molecular Epidemiology of
Prostate  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 202-512-1800 or on the Internet at the
URL address: http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

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
investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health
(NIH) individual research project grants (R01).  Because the nature and scope
of the research proposed in response to this PA may vary, it is anticipated
that the size of an award will also vary.

RESEARCH OBJECTIVES

Background

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
http://seer.cancer.gov/Publications/ProstMono/).  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 are expected to
be diagnosed in 1998.  Prostate cancer develops more rapidly with advancing
age than any other form of cancer and with the present trend toward an aging
population, its impact is a major public health concern.

The etiology of prostate cancer is obscure.  Clues may be derived from
descriptive epidemiology characterizing the steep slope of incidence with
advancing years, variation in race-specific and international incidence
patterns, and high prevalence of latent (clinically silent and histologically
apparent) carcinoma.  The most compelling hypothesis supports a hormonal
etiology based on the androgen-dependency of the prostate gland for growth and
function.  Studies in animal models have demonstrated the role of androgens in
the induction of prostate cancer.  Moreover, in humans, men castrated before
puberty do not develop prostate cancer, and prostate cancer has responded to
estrogen therapy.  Case-control studies of serum testosterone and other
hormones have thus far, however, reported inconsistent results, although it
has been reported that populations with high levels of serum testosterone have
an increased incidence of prostate cancer.

Past studies of familial aggregation and genetic analyses have indicated a
heritable component in risk.  Recent investigations have suggested that
prostate cancer risk is related to certain polymorphic genes that regulate
androgen metabolism, particularly the androgen receptor (AR) gene, and the
steroid 5-alpha-reductase type II (SRD5A2) gene.  In addition, there has been
interest in the cytochrome p450c17alpha (CYP17) gene, which encodes the enzyme
involved in testosterone biosynthesis, and the 3beta-hydroxysteroid
dehydrogenase type II (HSD3beta2) gene which encodes enzymes involved in
metabolism of dihydrotestosterone.  Furthermore, there is some evidence
relating hereditary prostate cancer to loci on chromosomes 1q and chromosome
X, while some cases appear to arise in association with familial breast cancer
in relation to BRCA1 and 2.

The consistently wide geographic variation in rates as well as results of
migrant studies suggest a role for environmental factors, including diet and
nutrition.  African American men have the highest incidence and mortality
rates in the world, almost 1.5 times higher than among U.S. whites and much
higher than among African populations.  The incidence varies widely around the
world:  a 65-fold difference exists between countries with the highest (blacks
in U.S. SEER:  137 per 100,000) and lowest (Shanghai, China:  2 per 100,000)
incidence rates  of prostate cancer.  In addition, immigrants from low-risk
countries (e.g., China or Japan) experience an increased risk after migrating
to a high-risk country (e.g., United States).  Evidence from case-control and
cohort studies has suggested that dietary fat may be associated with invasive
prostate cancer while certain micronutrients such as vitamin D, vitamin E, and
selenium may be protective.  The role of other environmental exposures (e.g.,
occupation, ionizing radiation, viruses) is inconclusive while the effects of
lifestyle factors (e.g., smoking, alcohol consumption, sexual behavior, body
mass, physical activity, vasectomy) have yet to be clarified.

The special characteristic of latent prostatic tumors, detected most often at
autopsy and estimated to affect one third of all males older than 50 years,
has remained an enigma in our understanding of the natural history and biology
of invasive prostate cancer.  Interestingly, there are no clear racial or
geographic differences in the occurrence of small intraprostatic foci of
latent cancer, whereas the prevalence of larger focal lesions parallels the
variations in mortality rates.  It has been hypothesized that environmental
factors may affect the transition of latent to invasive cancer by acting as
tumor promoters.  Little is known about the molecular events and processes
involved in the progressive transition to invasive cancer.  Although genetic
alterations in several chromosomes (e.g., 5, 8, 10, 16, 17, 18, and 22) have
been reported in relation to prostate carcinogenesis, the association with
tumor initiation and progression remains to be elucidated.

Research Goals and Scope

The purpose of this initiative is to stimulate innovative molecular
epidemiologic research into the origins and progression of prostate cancer. 
Interdisciplinary collaborations, which may include multicenter study sites as
well as joint effort between NIH/NCI intramural and extramural scientists, are
encouraged.  These collaborations may include utilization of shared laboratory
and specimen resources whenever possible.  Applications are welcomed from
investigators who are participating in ongoing collaborative organizations
such as the George M. O'Brien Kidney and Urologic Research Centers, the
Specialized Programs of Research Excellence in Prostate Cancer (SPORES), the
NIEHS Environmental Health Sciences Centers and the General Clinical Research
Centers (GCRCs).

Proposals to expand an ongoing epidemiologic study by the addition of a
laboratory component will be considered.  Transitional molecular epidemiology
studies characterizing and validating biomarkers while determining optimal
biological specimens and the most suitable procedures for collection,
processing, and storage are of particular interest.  Selected measurements or
biomarkers should be relevant to the processes of prostate carcinogenesis. 
Additionally, the utility of hormonal and surrogate or intermediate biomarkers
should be demonstrated with an evaluation of sensitivity, specificity, intra-
and inter-individual variability.

Investigations in understudied populations and in populations of contrasting
risk, including those who are residing outside of the U.S., are strongly
encouraged.  Establishment of cohorts of young and older men for participation
in longitudinal studies as well as of resources such as germline DNA
repositories and tumor tissue banks with clinical and epidemiologic databases
is highly recommended.  There is continued interest in ascertainment of high-
risk families, particularly African-American, to accelerate gene
identification and functional research.

This PA invites a range of interdisciplinary investigations, including
molecular epidemiologic, family, or population-based studies of prostate
cancer, utilizing available or new/novel biomarkers (e.g., biochemical,
molecular, cellular, genetic) and sources of specimens (e.g., prostate tissue,
prostatic fluid, blood components) whenever possible.  Examples of topics of
interest to the participating NIH institutes include, but are not limited to,
the areas listed below.

I.  NCI (in response to relevant recommendations of the NCI Prostate Cancer
Review Group, a committee of members of the scientific, medical, industrial,
and advocacy communities with the goal of developing a national plan for
pursuing scientific opportunities in prostate cancer research; refer to URL
address:  http://www.nci.nih.gov under "What's New")

o Etiology and tumor progression
- differences in genetic predisposition due to variations (polymorphisms) in
susceptibility and low-penetrance genes, DNA repair activities, cell cycle
progression, chromosome sensitivity to mutagens or in hormonal metabolism
- gene-environment interactions for understanding modification of prostate
cancer risk and influence on tumor progression
- suspected premalignant processes (e.g., morphological changes) as
independent or joint risk factors with, for example, hormones, nutrition,
genetic components, exogenous exposures that contribute to the transition from
latent to invasive cancer
- biologic characteristics in pre-cancerous lesions and tumor, such as
malignancy associated changes, heterogeneity or clusters of small foci, that
can better define the natural history of prostate cancer and predict prognosis

o Biomarkers
- assessment and validation of genetic and epigenetic markers that predict
tumor progression
from localized to disseminated prostate cancer
- validation of existing biomarkers of risk (e.g., androgen receptor
mutations, 5-alpha-reductase isoenzymes, epithelial cell receptors, hormonal
panels including insulin growth factor) in human populations with simultaneous
consideration of biological variables (e.g., age, ethnicity, genetic
predisposition, hormonal profiles, pre-existing disease) and lifestyle risk
factors
- identification, assessment, and validation of novel biomarkers for early
detection and diagnosis, including comparison with current indicators such as
PSA
- development and clinical validation of new biological markers associated
with prostate cancer biology (e.g., apoptosis, cell cycle control) with
determination of their role in responses to specific forms of systemic therapy
- development and validation of surrogate markers (e.g., nuclear chromatin
texture as quantitated by image analysis) that can serve as intermediate
endpoints for intervention or clinical trials testing preventive modalities

o Diet and lifestyle factors
- identification of dietary nutrients affecting prostate cancer risk and
mechanisms of action by which risk is altered
- pilot intervention studies of dietary nutrients (e.g., phytoestrogens,
micronutrients such as vitamins D and E, lycopene, selenium)
- role of lifestyle factors (e.g., smoking, alcohol intake), occupational and
environmental exposures (e.g., pesticides, viruses), sexual behavior,
anthropometry
- effect of dietary intake (e.g., fat, micronutrients such as vitamin D,
calcium, beta-carotene)  singly and jointly or interacting with endogenous
parameters (e.g., growth factors, steroid receptors, androgen conjugates)

o Primary prevention
- evaluation, including mechanisms of action and affected stages of
carcinogenesis and inhibition, of promising preventive agents based on
selection of tumor characteristics most amenable to preventive strategies
- identification and characterization of suspected premalignant processes
(e.g., prostatic intraepithelial neoplasia or PIN, dysplasia, atypical
adenomatous hyperplasia) as potential intermediate markers for intervention
trials

II. NIDDK

o Identification of risk factors (e.g., environmental, hormonal, viral
exposure, sexually transmitted diseases, lifestyle, ethnicity) associated with
benign prostatic hyperplasia or chronic prostatitis and clarification of their
possible relationships to the development of prostate cancer

III. NIEHS (reflecting the January 1998 announcement of the Environmental
Genome Project (EGP) to understand the role of environmental response genes on
human susceptibility to environmental agents; extensive background information
on the EGP is available at the following URL:
http://www.niehs.nih.gov/envgenom/home.htm)

o Elucidation of the role of environmental response genes (e.g., genes which
control the distribution and metabolism of toxicants, genes for DNA repair
pathways, genes for cell death and differentiation, receptor genes, etc.) in
the development of prostate cancer

o Enhanced understanding of the impact of occupational and environmental
exposures on the risk of prostate cancer including interactions with genetic
factors

o Exploration and elucidation of the role of timing of environmental exposures
during critical periods of normal prostate gland development (e.g., fetal
period, childhood, puberty) relevant to future risk of carcinogenesis
including, but not limited to:
(a) cellular, genetic, and hormonal effects of environmental exposures on
normal and abnormal prostate growth and development, and (b) mechanisms by
which environmental exposures acting as initiating or promoting agents at
various time periods affect the risk and latency of prostate cancer

SPECIAL REQUIREMENTS

Awardees under this PA are strongly encouraged to participate in two (2) one-
day meetings of investigators to be held in Bethesda, Maryland, during the
first and third years of the grant.  Program directors from the NCI, NIDDK,
and NIEHS will coordinate these meetings which will provide the opportunity
for principal investigators to discuss their proposals and work in progress as
well as any cross-disciplinary methodological and scientific issues. 
Applicants may request sufficient funds in the budget to accommodate expenses
for one to two participants at each meeting.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that 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 on the 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 at URL address: 
http://www.nih.gov/grants/guide/1994/94.03.18/notice-nih-guideline008.html).

Since this PA focuses on males as study participants, required inclusion of
women does not apply.

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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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 scientific and/or 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 "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 URL address: 
http://www.nih.gov/grants/guide/notice-files/not98-024.html.

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and the
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
a subsequent application, the information that it contains allows NIH staff to
estimate the potential review workload and avoid conflict of interest in the
review.  The letter of intent is to be sent to Dr. Kumiko Iwamoto at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at two application deadlines as indicated in this
program announcement.  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 20892-7710, telephone (301)
710-0267.  Email: [email protected].  The title and number of the program
announcement must be typed in Section 2a on the face page of the application
form and the YES box must be marked.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of a preceding grant application that requests $500,000 or more in
direct costs for any year are advised that he or she must contact the
Institute program staff before submitting the application.  Furthermore, the
applicant must obtain agreement from staff that the Institute will accept the
application for  review and, in a cover letter sent with the application,
include the name of the staff member (and Institute) who agreed to accept the
application.  Refer to the NIH Guide for Grants and Contracts, March 20, 1998
(URL address http://www.nih.gov/grants/guide/notice-files/not98-030.html).

Submit a signed, typewritten original of the application, including the
checklist, and five signed photocopies in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC-7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications that are complete will be evaluated for scientific
and technical merit by the Center for Scientific Review, in accordance with
the standard NIH peer review procedures.  As part of the initial merit review,
all applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed and
assigned a priority score.  Following scientific-technical review, the
applications will receive a second-level review by the appropriate national
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application 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 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 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?

The initial review group will also examine: the appropriateness of the
proposed project budget  and duration; the adequacy of plans to include
minorities and their subgroups and children as appropriate for the scientific
goals of the research and 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.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding decisions: 
quality of the proposed project as determined by peer review, availability of
funds, and Institute/program priorities.

INQUIRIES

Inquiries are encouraged, particularly during the planning phase of the grant
applications.  The opportunity to clarify any issues or questions from
potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Kumiko Iwamoto
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Suite 535
Bethesda, MD  20892
Telephone:  (301) 496-9600
FAX:  (301) 402-4279
Email:  [email protected]

Dr. Leroy Nyberg
Urology Program
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AS-13G
Bethesda, MD  20892
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  [email protected]

Dr. Gwen W. Collman
Chemical Exposures and Molecular Biology Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4980
FAX:  (919) 541-4937
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

William Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 250
FAX:  (301) 496-8601
Email:  [email protected]

Trude McCain
Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, 6AN-44J
Bethesda, MD  20892
Telephone:  (301) 594-8859
FAX:  (301) 480-4237
Email:  [email protected]

David L. Mineo
Grants Management Branch
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-7628
FAX:  (919) 541-2860
Email:  [email protected]

Direct inquiries regarding review matters to:

Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636A
Bethesda, MD  20892-7399
Rockville, MD  20850 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  [email protected]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.393, 93.849, and 93.894.  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 and Part 92.  This program is
not subject to intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.

The PHS strongly encourages all grant recipients 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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