Full Text CA-94-028

MOLECULAR EPIDEMIOLOGY OF PROSTATE CARCINOGENESIS

NIH GUIDE, Volume 23, Number 29, August 5, 1994

RFA:  CA-94-028

P.T. 34

Keywords: 
  Epidemiology 
  Cancer/Carcinogenesis 
  Biochemical Markers 


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

Letter of Intent Receipt Date:  October 17, 1994
Application Receipt Date:  November 23, 1994

PURPOSE

The Division of Cancer Etiology, National Cancer Institute (NCI);
Division of Kidney, Urologic, and Hematologic Diseases, National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and
Chemical Exposures and Molecular Biology Branch, 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, which 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 Request
for Applications (RFA), 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 202-783-3238.

ELIGIBILITY REQUIREMENTS

Domestic and foreign, non-profit and for-profit, public and private
institutions, such as colleges, universities, hospitals, research
laboratories, units of State and local governments, and agencies of the
Federal government are eligible to apply.  Foreign institutions and
organizations are not eligible for the First Independent Research
Support and Transition (FIRST) awards (R29) but may submit applications
for individual research project grants (R01); foreign applicants may
also participate in laboratory or clinical programs through subcontract
or consortium arrangements.  Minority and women investigators are
encouraged to apply.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) individual research project grants (R01), FIRST awards
(R29), and competing supplements (S01) to current R01 awards.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary NIH peer review
procedures.  However, should the NCI, NIDDK, and NIEHS determine that
there are sufficient continuing program needs, recipients of awards
under this RFA will be invited to submit competing continuation
applications for review.

It is anticipated that the size of an award will vary due to the nature
and scope of the proposed research with the average R01 award ranging
from $150,000 to $500,000 per year in total costs.  If direct costs
exceed $500,000 in any year, the funded study 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).  The
total project period for applications may not exceed five years.  The
total direct cost award for the five-year R29 grant period may not
exceed $350,000 and the direct cost award in any R29 budget period may
not exceed $100,000.  The earliest feasible start date for the initial
awards will be July 1, 1995.

FUNDS AVAILABLE

Approximately $3.75 million ($2,000,000 from NCI, up to $1,000,000 from
NIDDK and $750,000 from NIEHS) in total costs per year for five years
will be committed specifically to fund applications that are submitted
in response to this RFA.  It is anticipated that 8 to 12 awards will be
made.  This funding level is dependent on the receipt of a sufficient
number of applications of high scientific merit.  Although this program
is provided for in financial plans of the NCI, NIDDK, and NIEHS, the
award of grants pursuant to this RFA is contingent upon the
availability of funds at the time the awards are made.

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.  Its incidence rate has continued to increase
rapidly during the past two decades, especially in men over the age of
50 years, and 165,000 new incident cases comprising 27 percent of male
cancers were expected to be diagnosed in 1993 (1).  Prostate cancer
develops more rapidly with advancing age than any other form of cancer
and since 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
(2).  Case-control studies of serum testosterone and other hormones
have thus far, however, reported inconsistent results (3), although it
has been reported that populations with low levels of serum androgens
have a lower incidence of prostate cancer (4).

Although studies of familial aggregation and genetic analyses have
indicated a heritable component in risk (5), 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 (6).  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 (7-9)
while certain micronutrients such as vitamin D may be protective (10).
The role of other environmental exposures (e.g., occupation, ionizing
radiation, viruses) and 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 the 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 (11).  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 (12, 13).

An advisory workshop was organized and sponsored by the NCI and
co-sponsored by the National Institute on Aging (NIA), NIDDK, and NIEHS
in Bethesda, Maryland, on September 27, 1993.  The objective was to
determine the status of laboratory technology for endocrine biomarkers
and to identify directions for advancing molecular epidemiologic
research in the etiology of prostate cancer. The power of molecular
epidemiology studies, which incorporate laboratory advances in
molecular biology, genetics and biochemistry with epidemiologic study
designs, was emphasized.  Workshop recommendations identified research
needs in the following general areas:  (a) methodological
considerations in the measurement of hormonal profiles (e.g., androgen
and androgen metabolites) in body fluids; (b) studies of androgen
metabolism in prostatic tissue, including measures of 5-alpha-reductase
isoenzymes and androgen receptors; (c) assessment of biological markers
of genetic susceptibility, premalignant lesions (e.g., prostatic
intraepithelial neoplasia), and later progressive stages of the
carcinogenic process; (d) characterization of androgen receptor
mutations and other molecular alterations at the gene and cellular
levels; and (e) determination of risk associated with micronutrients
and macronutrients (e.g., fatty acids) and interactions with hormones
and hereditary factors. The objectives of this RFA were derived from
the major recommendations of the workshop.

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.  We 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:

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

b.  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:

a.  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;

b.  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.

SPECIAL REQUIREMENTS

Awardees under this RFA are strongly encouraged to participate in two
(2), one-day meetings to be held in Bethesda, Maryland, during the
second and fifth 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 work in
progress and to consider methodological and scientific issues.
Applicants may request sufficient funds in the budget to accommodate
expenses for one to two participants at each meeting.

STUDY POPULATIONS

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 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 Women in Study Populations, and 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 below.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are encouraged to submit, by October 17, 1994,
a letter of intent that includes a descriptive title of the proposed
research, the name and address of the principal investigator, the names
of other key personnel, participating institutions, number and title of
the RFA in response to which the application may be submitted, and
estimated amount of direct costs if anticipated to exceed $500,000 for
any year.  Potential applicants for research of this magnitude are
encouraged to contact the NCI prior to making detailed plans or
submitting their application(s).

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,
including the avoidance of conflict of interest.  The letter of intent
is to be sent to:

Dr. Kumiko Iwamoto
National Cancer Institute
Executive Plaza North, Suite 535
Bethesda, MD  20892
Telephone:  (301) 496-9600
FAX:  (301) 402-4279

APPLICATION PROCEDURES

Applications are to be submitted on form PHS 398 (rev. 9/91), available
at most institutional offices of sponsored research and from the Office
of Grants Information, Division of Research Grants (DRG), National
Institutes of Health, Room 449, Westwood Building, Bethesda, MD 20892,
telephone (301) 710-0267.  The format and instructions applicable to
research grant applications must be followed.

The RFA label available in the application form PHS 398 (rev. 9/91)
must be affixed to the bottom of the face page.  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 number and title of the RFA must be typed on line 2a of the face
page of the application and YES must be checked.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete and
will be returned without review.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed clear and single-sided photocopies in one
package to:

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

At the time of submission, send two additional copies of the
application to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Suite 636
Bethesda, MD  20892

Applications must be received by November 23, 1994.  If an application
is received after that date, it will be returned without review.  The
DRG will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application, and no application
will be accepted 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 for completeness by the DRG
and for responsiveness by the NCI, NIDDK, and NIEHS.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is determined to be nonresponsive to
the RFA, it will be returned without further consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NCI, NIDDK, and NIEHS in accordance with
the review criteria stated below. As part of the initial merit review,
a process (triage) may be used by the initial review group in which
applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications received
in response to this RFA.  Applications judged to be competitive will be
discussed and assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be promptly notified.  The peer review
will be followed by a second level of review by the National Cancer
Advisory Board, the National Advisory Council for Diabetes and
Digestive and Kidney Diseases, and the National Advisory Environmental
Health Sciences Council to consider the special needs of each
Institute.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications:

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.

The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each scored
application.

AWARD CRITERIA

The earliest anticipated date of award is July 1, 1995.  The following
will be considered in making funding decisions:

o  quality of the proposed project as determined by peer review;
o  availability of funds;
o  balance among research activities relevant to selected areas of
programmatic emphasis.

INQUIRIES

Written and telephone inquiries concerning this RFA and the opportunity
to clarify any issues or questions from potential applicants are
welcome.

Direct inquiries regarding programmatic issues to:

Dr. Kumiko Iwamoto
Epidemiology and Biostatistics Program
National Cancer Institute
Executive Plaza North, Suite 535
Bethesda, MD  20892
Telephone:  (301) 496-9600
FAX:  (301) 402-4279

Dr. David G. 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
Westwood Building, Room 3A-05B
Bethesda, MD  20892
Telephone:  (301) 594-7556
FAX:  (301) 594-7501

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:

Ms. Theresa A. Mercogliano
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 242
Bethesda, MD  20892
Telephone:  (301) 496-7800, ext. 243
FAX:  (301) 496-8601

Ms. Trude McCain
Division of Extramural Affairs
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 496-7467
FAX:  (301) 594-7594

Mr. 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 the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.

The Public Health Service (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.

References

1.  Boring CC, Squires TS, Tong T.  Cancer statistics, 1993.  CA Cancer
J Clin 1993; 43:7-26.

2.  Pienta KJ, Esper PS.  Risk factors for prostate cancer.  Ann Intern
Med 1993; 118:793-803.

3.  Nomura AMY, Kolonel LN.  Prostate cancer:  a current perspective.
Epid Rev 1991; 13:200-227.

4.  Ross RK, Bernstein L, Judd H.  Serum testosterone levels in young
black and white men.  J Natl Cancer Inst 1976;76:45-48.

5.  Steinberg GD, Carter BS, Beaty TH, et al.  Family history and the
risk of prostate cancer.  Prostate 1990; 17:337-347.

6.  Muir C, Waterhouse J, Mack T, et al, eds.  Cancer incidence in five
continents.  Vol 5. Lyon, France:International Agency for Research on
Cancer, 1987.  (IARC scientific publication no. 88).

7.  Giovannuci E, Rimm EB, Colditz GA, et al.  A prospective study of
dietary fat and risk of prostate cancer.  J Natl Cancer Inst 1993;
85:1571-1579.

8.  Ross RK, Shimizu H, Paganini-Hill A, et al.  Case-control studies
of prostate cancer in blacks and whites in southern California.  J Natl
Cancer Inst 1987; 78:869-74.

9.  Kolonel LN, Yoshizawa CN, Hankin JH.  Diet and prostatic cancer:
a case-control study in Hawaii.  Am J Epidemiol 1988; 127:999-1012.

10.  Corder EH, Guess HA, Hulka BS, et al.  Vitamin D and prostate
cancer: a prediagnostic study with stored sera.  Cancer Epidemiol,
Biomarkers & Prev 1993; 2:467-472.

11.  Chiarodo A.  National Cancer Institute roundtable on prostate
cancer: future research directions.  Cancer Res 1991; 51:2498-2505.

12.  Bova GS, Carter BS, Bussemakers MJG, et al.  Homozygous deletion
and frequent allelic loss of chromosome 8p22 loci in human prostate
cancer. Cancer Res 1993; 53:3869-3873.

13.  Carter BS, Ewing CM, Ward WS, et al.  Allelic loss on chromosomes
10q and 16q in human prostate cancer.  Proc Natl Acad Sci 1990;
87:8751-8755.

.

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