Full Text PA-95-084

MOLECULAR EPIDEMIOLOGY OF PROSTATE CARCINOGENESIS

NIH GUIDE, Volume 24, Number 30, August 18, 1995

PA NUMBER:  PA-95-084

P.T. 34

Keywords: 
  Urogenital System 
  Epidemiology 
  Cancer/Carcinogenesis 
  Etiology 
  Biochemical Markers 


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

PURPOSE

The Division of Cancer Etiology of the National Cancer Institute
(NCI), the Division of Kidney, Urologic, and Hematologic Diseases of
the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), and the Division of Extramural Research and Training of the
National Institute of Environmental Health Sciences (NIEHS) invite
investigator-initiated research grant applications for molecular
epidemiologic studies to further the understanding of prostate cancer
etiology.  The purpose of this initiative is to stimulate the use of
biochemical and molecular markers for identifying and assessing risk
factors that could lead to effective prevention strategies.

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 Program
Announcement (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.

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.
Foreign institutions and organizations are not eligible for the First
Independent Research Support and Transition (FIRST) awards (R29), but
may participate in laboratory or clinical programs through
subcontract or consortium arrangements.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) individual research project grants (R01) and FIRST (R29)
awards.  NCI-funded investigators with ongoing R01, Method to Extend
Research in Time (MERIT) (R37), and Program Project (P01) awards who
are expanding the scope of their work and have at least one year of
support remaining from the anticipated date of award may apply for
competing supplement (S1) awards for the duration of the ongoing
grant.

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.  For FIRST awards, the total direct cost award for the
five-year period may not exceed $350,000; the direct cost award in
any budget period may not exceed $100,000.  Applications assigned to
the NCI with direct costs exceeding $500,000 in any year, may be
considered for an award as a cooperative agreement (U01) (refer to
NIH Guide, Vol. 22, No. 43, November 26, 1993 and Vol. 22, No. 45,
December 17, 1993).

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.  The incidence rate of prostate cancer has
continued to increase rapidly during the past two decades, especially
in men more than 50 years old, and 165,000 new incident cases
comprising 27 percent of male cancers were expected to be diagnosed
in 1993.  Prostate cancer develops more rapidly with advancing age
than any other form of cancer, and since a larger proportion of the
population is aging, 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 in the elderly, variation in race-specific and
international incidence patterns, and high prevalence of latent
(histologically apparent and clinically silent) 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 thus far, however, have had
inconsistent results, although it has been reported that populations
with low levels of serum androgens have a lower incidence of prostate
cancer.

Although studies of familial aggregation and genetic analyses have
indicated a heritable component in risk, the wide geographic
variation in rates as well as 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, two-fold higher than among U.S. whites and much higher than
among African populations.  The incidence varies widely around the
world:  a 50-fold difference exists between countries with the
highest (blacks in Detroit, Michigan:  91.1 per 100,000) and lowest
(Shanghai, China:  1.8 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 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, 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.
To date, genetic alterations in chromosomes 5q, 8p, 10q, 16p, and 17p
have been reported in relation to prostate carcinogenesis.

Research Goals and Scope

The purpose of this initiative is to stimulate innovative molecular
epidemiologic research into the origins of prostate cancer, including
the biological basis for the striking increase in prostate cancer
incidence with age.  Collaborations of several disciplines and
research institutions are encouraged with utilization of shared
laboratory and specimen resources whenever possible.  Applications
will be 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).  It is suggested that the collaborative organization be
identified as the resource for conducting the proposed research, and
a letter of agreement from the program director or principal
investigator be included with the application.

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, there is a
need for demonstration of the utility of hormonal biomarkers with an
evaluation of sensitivity, specificity, intra- and inter-individual
variability.  NCI, NIEHS, and NIDDK strongly encourage investigations
in understudied populations and in study populations of contrasting
risk.  Projects will be evaluated on the basis of their potential for
enhancing understanding of prostate cancer etiology.

The initiative invites a range of epidemiologic and interdisciplinary
investigations of prostate cancer including, but not limited to:

o  Epidemiologic studies to:

- evaluate prostate cancer risk of lifestyle factors (e.g., smoking,
alcohol intake), occupation (e.g., cadmium and zinc exposures, rubber
industry, farming), environmental hazards (e.g., organochlorine
compounds including DDT, PCBs, and dioxins or other pesticides), and
dietary intake (e.g., fatty acids, vitamins A, D, and E) utilizing
available biomarkers and sources of specimens (e.g., prostate tissue,
prostatic fluid, blood components) whenever possible;

- assess interactions of the above factors or their
interrelationships with biochemical parameters (e.g., growth factors,
prolactin, steroid receptors, androgen conjugates, 5-alpha-reductase
isoenzymes);

o  Epidemiologic studies to identify risk factors (e.g.,
environmental, hormonal, viral exposure, sexually transmitted
diseases, lifestyle, ethnicity) associated with benign prostatic
hyperplasia or chronic prostatitis and to clarify their possible
relationships to prostate cancer;

o  Population-based studies of the relationship between prostatic
intraepithelial neoplasia, dysplasia, atypical hyperplasia, and
invasive prostate cancer;

o  Analytic epidemiologic studies utilizing developed markers (e.g.,
biologic, biochemical, morphologic) to identify premalignant
processes or risk factors (e.g., hormonal, environmental) that
contribute to prostate carcinogenesis, including the transition from
latent to invasive cancer;

o  Studies to further develop identified biomarkers (e.g., androgen
receptor mutations, 5-alpha-reductase isoenzymes, epithelial cell
receptors) for application in epidemiologic research by
characterization and validation (in the laboratory and in humans)
including consideration of biologic variables, e.g., age, genetic
predisposition, ethnicity, nutritional status, hormonal profiles,
preexisting disease and lifestyle;

o  Experimental laboratory or population-based studies to explore and
elucidate the role of timing of environmental exposures during
critical developmental and other time periods (e.g., fetal period,
the window from birth to puberty, puberty, after castration or
vasectomy) of the prostate gland relevant to future risk of
carcinogenesis including, but not limited to:  (a) cellular, genetic,
and hormonal effects of environmental factors on normal and abnormal
prostate growth and development, and (b) mechanism of how
environmental exposures acting as initiating or promoting agents
during time periods of interest affect the latency of prostate
cancer;

o  Biochemical epidemiologic studies to:

- validate and compare prostate tissue levels of hormones (e.g.,
androgens, estrogens), their metabolites and receptors with other
sources of specimens such as blood components and prostatic fluid;

- evaluate panels of circulating hormones (e.g., dihydrotestosterone
[DHT] and its precursors, testosterone, DHEAS, DHEA, androstenedione
and its metabolites such as DHT sulfate, DHT glucuronide, 3-alpha-
diol glucuronide) in populations of varying risk, including men
younger than 50 years old;

o  Molecular epidemiology studies to explore differences in genetic
predisposition to prostate cancer due to variations in susceptibility
genes, hormone metabolism, DNA repair activities, chromosome
sensitivity to mutagens or other factors.

INCLUSION OF 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 new policy results from the NIH
Revitalization Act of 1993 (Section 492B of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Minorities in Study Populations) which have been in
effect since 1990.  The new policy contains some new provisions that
are substantially different from the 1990 policies.

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 was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit. Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
Room 3032, MSC-7762, Bethesda, MD 20892-7762, telephone (301)
710-0267.  The title and number of the program announcement must be
typed in Section 2 on the face page of the application.

FIRST applications must include the three sealed letters of reference
attached to the face page of the original application, or the
applications will be considered incomplete and will be returned to
the applicant.

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

Division of Research Grants
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 and responsive
to the program announcement will be evaluated for scientific and
technical merit by an appropriate peer review group convened 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, assigned a priority
score, and receive a second level review by the appropriate national
advisory council or board.

Review Criteria

o  scientific, technical, or medical significance and originality of
the proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the principal
investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of resources necessary to perform the research;

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

o  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 will also be
evaluated.

AWARD CRITERIA

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

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 Etiology
National Cancer Institute
Executive Plaza North, Suite 535
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279
Email:  [email protected]

Dr. David Longfellow
Chemical and Physical Carcinogenesis Branch
National Cancer Institute
Executive Plaza North, Suite 700
Bethesda, MD  20892
Telephone:  (301) 496-5471
FAX:  (301) 496-1040

Dr. Ralph L. Bain
Urology Program
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AS-19B
Bethesda, MD  20892
Telephone:  (301) 594-7713
FAX:  (301) 480-3510

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) 541-2843

Direct inquiries regarding fiscal matters to:

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

Trude McCain
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-44J
Bethesda, MD  20892
Telephone:  (301) 594-8856
FAX:  (301) 480-3504

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

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 HHS policies and grant regulations.  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 to provide a smoke-
free workplace and promote the non-use of all tobacco products.  This
is consistent with the PHS mission to protect and advance the
physical and mental health of the American people.  In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of the facility)
in which regular or routine education, library, day care, health care
or early childhood development services are provided to children.

.

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