RELEASE DATE:  February 13, 2002 (see reissuance RFA-CA-04-004)

RFA:  RFA-CA-03-003


National Cancer Institute (NCI)

Letter of Intent Receipt Date:  June 12, 2002
Application Receipt Date:       July 17, 2002


o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


The Division of Cancer Prevention, National Cancer Institute (NCI), invites 
applications for new R01 grants to foster probing investigations that will 
define molecular targets for nutrients and further, connect those targets 
with phenotypic outcome in prostate cancer prevention.   Candidate targets 
for examination should not only be influenced by a nutrient but also be 
closely linked to a significant proportion of prostate tumors, be relatively 
specific for prostate cancer across various genetic backgrounds, and be 
related to changes in tumor risk and/or behavior when modified.  
Investigators are encouraged to use in vitro and in vivo studies with various 
levels of target expression and to address confounding factors that influence 
the overall physiological response to changes in a given molecular target.    



Although the etiology of prostate cancer is poorly understood, a variety of 
dietary components spanning the gamut of essential and non-essential 
nutrients are proposed to influence prostate cancer risk.  The impact of 
specific dietary components on prostate tissue likely depends on a host of 
genetic and epigenetic processes that influence growth, development and 
differentiation.  Phenotypic changes may arise directly from alterations in 
specific genetic and/or epigenetic events or indirectly from changes in 
hormonal balance, immunocompetence, or the activity of other bioregulators.

Possible Molecular Targets for Nutrients

Advances in biology have identified several regulatory sites that may serve 
as potential molecular targets for prostate cancer prevention.  Evidence 
already exists that nutrients may alter prostate cancer risk and tumor cell 
behavior by influencing hormonal regulation, cell signaling, cell cycle 
control, apoptosis, differentiation, and carcinogen metabolism.  

1. Hormonal Regulation
Factors involved in hormonal regulation may serve as targets since sex 
hormones are known to have a pivotal role in growth, differentiation and 
function of prostate tissue.  One of the central elements of hormonal 
regulation is the androgen receptor (AR), a member of the superfamily of 
nuclear receptors.  The transcriptional activation domain of the androgen 
receptor gene contains a polymorphic CAG repeat sequence.  Variability in the 
length of this sequence is recognized to influence the transcriptional 
activity of the androgen receptor.  Men with shorter CAG repeats have been 
reported to be more androgen sensitive and to have a high risk for distant 
metastatic and fatal prostate cancer.  Varying lengths of CAG-repeats of the 
androgen receptor do not appear to fully explain racial differences in 
clinical prostate cancer incidence suggesting other factors such as diet may 
be involved.  Evidence for a role of diet comes from observations that 
caloric restriction reduces the loss of hepatic AR mRNA levels caused by 
aging.   Resveratrol, found in grapes and peanuts, was also shown to repress 
the expression of AR, which in turn lowered the levels of prostate-specific 
antigen (PSA) and p21(WAF1).  Expanding these findings to several factors 
influencing other processes of prostate cancer cells will clarify if AR can 
serve as a molecular target or surrogate marker for nutrients.  

In some experimental models, androgen deprivation results in a spontaneous 
increase in estrogen receptor (ER) expression in prostatic tissue.  Estrogen 
receptor has two subtypes, alpha and beta.  ER alpha and ER beta were shown 
to signal in opposite ways when complexed with the natural ligand, 17 beta-
estradiol from an AP1 site.  Prostate cells express ER beta abundantly, not 
ER alpha while uterine cells express ER alpha dominantly.  ER beta from the 
prostate has a high affinity for genistein, a major soy isoflavone, which has 
several biological effects including a protein tyrosine kinase (PTK) 
inhibitor, an antioxidant, an inhibitor of angiogenesis, a blocker of 
topoisomerase II, an arrester of the cell cycle at the G2/M stage as well as 
acting as a phytoestrogen.  This phytochemical has been shown to inhibit the 
growth of LNCaP human prostatic cancer cells in culture (IC50 = 50 ?M).  It 
also has been shown to reduce one of the most fundamental biomarkers for 
prostate cancer, PSA, as well as modulate other proliferation and cell cycle 
related factors including PCNA, p21 (WAF1) and p27 (Kip1).  Further studies 
are needed to determine which of these molecular targets is primarily 
responsible for genistein's antiproliferative effects on prostate cancer cells. 

2. Cell Signaling
Cells are constantly responding to numerous extracellular signals and 
coordinating these complex messages into a collection of responses that may 
be modulated by dietary components.  One critical aspect of intracellular 
signaling is regulation of key cell functions by lipid mediators, 
particularly phosphatidylinositol (PI).  Evidence already exists that the 
composition of membrane PI that is closely linked to phosphatidylinositol 3-
kinase (PI3K) signaling pathway, depends on dietary lipids.  More 
specifically, increased prostate cancer cell proliferation and prolongation 
of survival has been observed following linoleic and arachidonic acid 
treatment of cells in culture.  Enhanced PI3K activity through 
hydroxyeicosatetraenoic acid (HETE) and prostaglandin E2 formation may relate 
to this elongated cancer cell survival.  Genistein is known to inhibit growth 
factor receptors that lie upstream from the PI3K signaling pathway, which may 
account for the growth suppressive effect of this soy component.  Evidence 
from these studies may explain the observations that consumption of a low fat 
diet supplemented with soy protein and isoflavonoids markedly retards the 
growth of the human androgen-sensitive prostate cancer cells (LNCaP) 
transplanted in severe-combined immunodeficient (SCID) mice.  

PI3K is also important in the Akt/PKB pathway that is initiated by survival 
factors including insulin-like growth factor I (IGF-I).  Evidence exists that 
circulating blood levels of IGF-I decrease with increased blood lycopene, a 
dietary antioxidant found in red tomatoes.  This finding is consistent with 
data from the Physicians Health Study that indicated an inverse relationship 
between circulating blood levels of lycopene and aggressive prostate cancer 
incidence.  More probing studies will delineate the dynamics among nutrients 
that modulate cell signaling pathway.  

3. Apoptosis/Cell Cycle
Apoptosis, also known as programmed cell death, is one of the important 
pathways through which nutrients can inhibit the growth of cancer cells.  
This pathway is regulated by the Bcl2 gene family that contains individual 
members that can suppress (e.g. Bcl2) or promote (e.g. Bax) cell death.  
While this process is very complex, part of apoptosis can be mediated by 
deregulation in cell cycle progression that is governed by a family of 
cyclin-dependent kinases (CDKs).  Evidence exists that a variety of nutrients 
modulate a number of genes or gene products that are involved in this 
process.  For example, (-)-epigallocatechin-3-gallate (EGCG), the major 
polyphenolic constituent present in green tea, imparted apoptotic effects 
against human prostate cancer cells by up-regulating CDK inhibitors including 
p21(WAF1) and p27(Kip1) with the concomitant increase in Bax and the decrease 
in Bcl2 levels.  Similar effects of this phytochemical were demonstrated in 
transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which 
spontaneously develops metastatic prostate cancer.  In this study oral 
administration of green tea polyphenols caused significant apoptosis of 
prostate cancer cells, which possibly resulted in several phenotypic changes 
including significant delay in primary tumor incidence as assessed by 
magnetic resonance imaging (MRI), almost complete inhibition of distant site 
metastases, and significant decrease in prostate weight compared with water-
fed TRAMP mice.  Other evidence for the involvement of nutrients in this 
pathway comes from the treatment of prostate cancer cells with indole-3-
carbinol, a component of cruciferous vegetables.  When PC3 cells were 
supplemented with indole-3-carbinol, cells were arrested at the G1 cell cycle 
with the up-regulation of p21(WAF1) and p27(Kip1), accompanied with the 
increased Bax and the decreased Bcl2 levels.  While these findings support 
the epidemiologic observations that green tea and cruciferous vegetables may 
reduce prostate cancer risk in humans, more probing studies are needed to 
determine the molecular targets for these dietary constituents.

4. Differentiation
Vitamin A and D receptors, ligand-inducible nuclear transcription factors, 
have an important function to promote differentiation in various cells.  
Polymorphism in the vitamin D receptor (VDR) gene has been linked with 
prostate cancer risk.  Adding 1,25-dihydroxyvitamin-D3 (1,25 D) inhibits the 
growth of primary cultured human prostatic cells, and their invasion.  These 
effects may relate to changes in surface adhesion molecules or to other 
biological events.  Since the VDR heterodimerizes with the retinoid X 
receptor, the intake of retinoids and carotenoids may also influence the 
overall response.  Currently, insufficient information exists about the 
influence of vitamin A or vitamin D binding to normal or polymorphic 
receptors on transcriptional regulation and the subsequent modulation of cell 
growth and invasion of prostate cancer cells.  

The inverse relationship between calcium intake and blood levels of the 1,25-
D suggests that high calcium intake may increase prostate cancer risk.  
Ecologic data support this hypothesis.  The biological basis for this 
observation remains to be determined.  Examination of genes involved with 
calcium channels or other calcium sensitive pathways may help explain the 
role of this nutrient in prostate cancer development.

5. Carcinogen Metabolism
Accumulating research suggests that normal prostate cells are sensitive to 
genome-damaging carcinogens.  For example, 2-amino-1-methyl-6-
phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen 
present in well-done meat that has been reported to increase prostate cancer 
in rats.  Bioactivated PhIP exerts its mutagenic and carcinogenic effects by 
causing DNA damage in several tissues including prostate.  Recent 
experimental evidence demonstrated that induction of glutathione S-
transferase pi (GSTP1), a major class of GSTs, protected cells against PhIP 
induced DNA damage in human prostate cancer cells (LNCaP).  GSTP1 expression 
is silenced by the methylation process in prostatic adenocarcinoma and high-
grade prostatic intraepithelial neoplasia (HGPIN).  What impact dietary 
methyl donors have on the GSTP1 methylation and the subsequent carcinogen 
detoxification in prostate cancer remains to be determined. 

Animal Models Offer Unique Possibilities

The frequency of spontaneous prostate cancer is rare in mammals except for 
humans and dogs.  Carcinogen or transgenic models that provide some clues 
about preventative and therapeutic strategies have been developed.  During 
the past decade the Lobund-Wistar rats have been used as a model since they 
exhibit prostatic intraepithelial neoplasia and are predisposed to 
metastasizing adenocarcinomas following treatment with methylnitrosourea.  
The supplementation with phytochemicals, such as genistein, has been reported 
to lower tumors in this model.  More recently a variety of genetically 
defined mice, including transgenics and gene knockouts, have been developed, 
which display prostatic hyperplasia and dysplasia.  The availability of these 
mice may provide an important tool for characterizing molecular targets for 
nutrients.  Recent studies demonstrate that a low saturated fat diet or 
supplementation with green tea polyphenols suppress tumor incidence and 
metastasis in the TRAMP model. 

Knockout animals are beginning to be used to examine genes that may influence 
the ability of nutrients and/or drugs to alter the cancer process.  For 
example, 1,2-dithiole-3-thione found in alliaceous and cruciferous plants is 
known to be a potent inhibitor of chemically induced tumors.  The molecular 
target for this compound became clearer as a result of recent studies using 
an nrf2 knockout mouse model.  Induction of several phase II enzymes by 1,2-
dithiole-3-thione was completely abrogated in nrf2 knockout mice treated with 
model carcinogens.  The expanded use of animal models should provide unique 
opportunities for explaining the impact of individual dietary components on 
the observed variation in prostate cancer incidence.

Objectives and Scope

This Request for Applications (RFA) seeks to promote research to clarify the 
molecular basis by which nutrients retard prostate cancer.  Connecting 
molecular targets for nutrients with phenotypic outcome offers the exciting 
opportunity for basic research and for explaining variation in observed 
responses within and across populations and hopefully for those who will 
benefit most from dietary intervention strategies.  The object of this RFA is 
to identify and characterize molecular targets for nutrients in normal and 
neoplastic prostate cells.  Since targets are not static but dynamic 
processes that must be examined over a full range of expression, 
investigators are encouraged to use various levels of target expression to 
determine the precise role of nutrients in prostate cancer prevention.  

Nutrients may modify simultaneously more than one process including 
carcinogen metabolism, hormonal balance, cell signaling, cell cycle control, 
apoptosis, and differentiation.  Therefore, it is important that an 
integrative approach is taken to these investigations.  Investigators are 
encouraged to address confounding factors that may influence the overall 
physiological response to changes in a given molecular target.  For example 
alterations in p27(Kip1) that arise from direct or indirect interactions with 
nutrients may bring about fluctuations in various factors in signaling 
pathways such as protein tyrosine kinases, survival pathways such as IGF-
1/PI3K/Akt, oncogenes including c-myc, tumor suppressor genes including pRb, 
apoptosis related genes including Bcl2, cell senescence including telomerase 
activity, and inflammation related transcription factors including NF-kappaB. 

Several nutrients may modify the same target.  For example, p27(Kip1)  could 
be a potential molecular target for various nutrients including genistein, 
EGCG, indole 3-carbinol, and resveratrol.  Investigators will be encouraged 
to define nutrients in terms of their relative effectiveness, dose-
dependency, temporality, consistency, and specificity.  

The use of chemically induced, transgenic, and knockout animal models offers 
additional opportunities for unraveling the specific role of nutrients beyond 
that possible when cell culture systems are used.  The use of transgenic 
and/or conditional knockout models available through the Mouse Models for 
Human Cancer Consortium (MMHCC, is encouraged.  
For example studies that examine the impact of suppressed or exaggerated 
activities of genes regulating nutrient absorption or metabolism may provide 
clues to variation in response.  Additionally, transcriptional factors, 
cofactors and other regulators that influence a specific target may be 
appropriate for manipulation in chemically induced or transgenic models used 
to define the role of nutrients.

The use of a variety of molecular technologies including genetic manipulation 
of animal models, cDNA/tissue microarray, serial analysis of gene expression 
(SAGE), and proteomic tools are encouraged.  Investigators are encouraged to 
utilize NCI's Cancer Genome Anatomy Project database on human and mouse 
genomics including expressed sequence tags (ESTs), gene expression patterns, 
single nucleotide polymorphisms (SNPs), cluster assemblies, and cytogenetic 
information (

The following are viewed as relevant examples for the development of the 
R01 application.

1) Can variation in AR or ER explain the ability of soy isoflavones to retard 
prostate cancer?
2) Can IGF-1, PI3K, and Akt account for the effect of dietary fatty acids on 
prostate tumor growth promotion?
3) Are Bax and Bcl2 responsible for the efficacy of green tea polyphenols and 
indole 3 carbinol to retard prostate cancer cell growth?  
4) Does modification of antioxidant response element (ARE) explain the 
ability of dietary antioxidants to reduce prostate cancer incidence?
5) Can GSTP1 methylation be influenced by dietary methyl donors and 
ultimately modify prostate cancer risk?


Applications in response to the RFA must address the following areas:  (a) 
The effects of nutrients on growth and survival in prostate cancer cells will 
need to be characterized in terms of dose-dependency and temporality.  (b) 
Targets for these nutrients should be examined over a range of expression, 
ideally from null to overexpression.  


This RFA will use NIH R01 award mechanism.  As an applicant you will be 
solely responsible for planning, directing, and executing the proposed 
project.  The anticipated award date is April 2, 2003.

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats 
(see  Specifically, 
if you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.


NCI intends to commit approximately $2.5 million in FY 2003 to fund 4 to 6 
new grants in response to this RFA. An applicant may request a project period 
of up to 5 years.  Because the nature and scope of the proposed research will 
vary from application to application, it is anticipated that the size and 
duration of each award will also vary. Although the financial plans of the 
NCI provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. In addition to the current RFA 
solicitation, it is anticipated that this RFA will be reissued one 
additional time.


You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

All current policies and requirements that govern the research grant programs 
of the National Institutes of Health (NIH) will apply to grants awarded under 
this RFA.  Awards under this RFA to foreign institutions will be made only in 
accordance with PHS policy governing such awards.


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   


We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Dr. Young S. Kim
Division of Cancer Prevention
National Cancer Institute 
6130 Executive Blvd., Room 3156
Bethesda, MD  20892
Telephone:  (301) 496-0126
FAX:  (301) 480-3925

Direct inquiries regarding peer review issues to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8041, MSC-8329
Rockville, MD  20852 (express courier)
Bethesda MD  20892-8329
Telephone:  (301) 496-3428
Fax:  (301) 402-0275

Direct inquiries regarding fiscal matters to:
Ms. Eileen M. Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Plaza South, Room 243
Bethesda, MD  20892
(For Express mail, use Rockville, MD  20852)
Telephone: (301) 496-8791
FAX:  (301) 496-8601


Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 NCI staff to estimate the potential review workload and plan 
the review.
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Dr. Young S. Kim
Division of Cancer Prevention
National Cancer Institute 
6130 Executive Blvd., Room 3156
Bethesda, MD  20892
Telephone:  (301) 496-0126
FAX:  (301) 480-3925


Letter of Intent Receipt:         June 12, 2002
Application Receipt:              July 17, 2002
Peer Review Date:                 November/December, 2002
Review by NCAB Advisory Board:    February 2003
Earliest Anticipated Start Date:  April 02, 2003


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at  

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/01) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.  The RFA label is also available at:

SENDING AN APPLICATION TO NIH:  Submit a signed, typewritten original of the 
application, including the checklist, and three signed, exact, single-sided 
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)

At the time of submission, two additional copies of the application must be 
sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD  20892-8329
Rockville, MD  20852 (for express/courier service)

APPLICATION PROCESSING:  Applications must be received by JULY 17, 2002.  If 
an application is received after that date, it will be returned to the 
applicant without review.  The Center for Scientific Review  (CSR) 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.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of substantial revisions of applications already reviewed, but 
such applications must include an introduction addressing the previous critique.  


Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by the NCI.  Incomplete and/or non-responsive applications 
will be returned to the applicant 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 Division of Extramural Affairs (DEA) at NCI in accordance 
with the review criteria stated below.  As part of the initial merit review, 
all applications will:

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score, and receive
a second level review by the National Cancer Advisory Board (NCAB).

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.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The scientific review group will address and consider each of these criteria 
in assigning the overall score, weighting them as appropriate for each 
application.  Your 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, you may propose to carry out important work 
that by its nature is not innovative but is essential to move a field forward.
SIGNIFICANCE: Does this study address linkages between molecular targets for 
nutrients and phenotypic outcome in prostate cancer ?  If the aims of the 
application are achieved, how will  the nutrients that modify specific 
molecular targets be used for dietary intervention studies in prostate 
cancer?  Will these  research projects  advance the field of nutrition from 
observational to more probing studies?

APPROACH: Are the conceptual framework, design, methods, and analyzes 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?  Does the applicant propose to study various levels of 
target expression to determine the precise role of nutrients in prostate 
cancer prevention?  Does the applicant plan to examine the effects of 
nutrients on  candidate targets using in vivo system?  Does the applicant 
propose to characterize the temporal and dose effects of nutrient(s) on their 
molecular targets?

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?  

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)?  

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 ?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, animals, 
or the environment, to the extent they may be adversely affected by the 
project proposed in the application.

o INCLUSION:  The adequacy of plans to include subjects from both genders, 
all racial and ethnic groups (and subgroups), and children as appropriate for 
the scientific goals of the research.  This study deals with prostate cancer, 
as such human subjects can be obtained only from men.  Nevertheless, this 
issue should be addressed clearly in the application form. Plans for the 
recruitment and retention of subjects will also be evaluated. (See Inclusion 
Criteria included in the section on Federal Citations, below)

o DATA SHARING:  The adequacy of the proposed plan to share data.

o BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

Applications recommended by the National Cancer Advisory Board will be 
considered for award based upon the following:  

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.


involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the principal 
investigator/project manager or NCI program staff or a Data and Safety 
Monitoring Board (DSMB).  These monitoring activities are distinct from the 
requirement for study review and approval by an Institutional review Board 
(IRB).  For details about the Policy for the NCI for Data and Safety 
Monitoring of Clinical trials see:  For Phase I and II 
clinical trials, investigators must submit a general description of the data 
and safety monitoring plan as part of the research application.  See NIH 
Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I 
and II Trials" for additional information:  Information 
concerning essential elements of data safety monitoring plans for clinical 
trials funded by the NCI is available:

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
a complete copy of the updated Guidelines are available at  
The amended policy incorporates: the use of an NIH definition of 
clinical research; updated racial and ethnic categories in compliance with 
the new OMB standards; clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398; and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

The NIH maintains a policy 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 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 is available at

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at  A 
continuing education program in the protection of human participants in 
research in now available online at:

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned 
without review. 

Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This 
RFA is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93. 393 (Cancer Cause & Prevention Research) 
and is not subject to the intergovernmental review requirements of Executive 
Order 12372 or Health Systems Agency review.  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 NIH grants policies 
described at and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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