MOLECULAR TARGETS FOR NUTRIENTS IN PROSTATE CANCER PREVENTION
RELEASE DATE: April 24, 2003
RFA: CA-04-004
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: No. 93.393
LETTER OF INTENT RECEIPT DATE: June 19, 2003
APPLICATION RECEIPT DATE: July 17, 2003
This RFA is a reissue of RFA-CA-03-003, which was published in the NIH Guide
on February 13, 2002.
THIS RFA CONTAINS THE FOLLOWING INFORMATION
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
PURPOSE
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.
RESEARCH OBJECTIVES
Background
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, http://emice.nci.nih.gov/) 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 (http://cgap.nci.nih.gov/).
The following are viewed as relevant examples for the development of the R01
application. Note that these are examples only and are not intended to be
inclusive.
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?
RESEARCH REQUIREMENTS
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.
MECHANISM OF SUPPORT
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 1, 2004. Applications that are
not funded in the competition described in this RFA may be resubmitted as NEW
investigator-initiated applications using the standard receipt dates for NEW
applications described in the instructions to the PHS 398 application.
This RFA uses just-in-time concepts. It also uses the modular as well as the
non-modular budgeting formats (see
https://grants.nih.gov/grants/funding/modular/modular.htm). 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.
FUNDS AVAILABLE
NCI intends to commit approximately $2.5 million in FY 2004 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.
ELIGIBLE INSTITUTIONS
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
o Faith-based or community-based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
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.
WHERE TO SEND INQUIRIES
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
Email: yk47s@nih.gov
o 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
Email: ncirefof@dea.nci.nih.gov
o Direct inquiries regarding fiscal matters to:
Ms. Kathryn Dunn
Grants Administration Branch
National Cancer Institute
6120 Executive Plaza South, Room 243
Bethesda, MD 20892
(For Express mail, use Rockville, MD 20852)
Telephone: (301) 846-8629
FAX: (301) 846-5720
Email: dunnk@gab.nci.nih.gov
LETTER OF INTENT
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
Rockville, MD 20852 (express courier)
Telephone: (301) 496-0126
FAX: (301) 480-3925
Email: yk47s@nih.gov
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant application
instructions and forms (rev. 5/2001). The PHS 398 is available at
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications
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,
https://grants.nih.gov/grants/funding/phs398/phs398.html) includes step-by-
step guidance for preparing modular grants. Additional information on
modular grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
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:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO NIH: Submit a signed, typewritten original of the
application, including the checklist, and three signed, exact, 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)
APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE
WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries
(i.e. FEDEX, UPS, DHL, etc.) (https://grants.nih.gov/grants/guide/notice-files/
NOT-CA-02-002.html) This change in practice is effective immediately.
This policy is similar to and consistent with the policy for applications
addressed to Centers for Scientific Review as published in the NIH Guide
Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.
APPLICATION PROCESSING: Applications must be received on or before July 17,
2003. If an application is received after that date, it will be returned to
the applicant without review.
Although there is no immediate acknowledgement of the receipt of an
application, applicants are generally notified of the review and funding
assignment within 8 weeks.
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.
However, when a previously unfunded application, originally submitted as an
investigator-initiated application, is to be submitted in response to an RFA,
it is to be prepared as a NEW application. That is the application for the
RFA must not include an Introduction describing the changes and improvements
made, and the text must not be marked to indicate the changes. While the
investigator may still benefit from the previous review, the RFA application
is not to state explicitly how.
PEER REVIEW PROCESS
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 Activities (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.
o Receive a second level review by the National Cancer Advisory Board (NCAB).
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 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, the following
items will be considered in the determination of scientific merit and the
priority score:
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human
subjects and protections from research risk relating to their participation
in the proposed research will be assessed. (See criteria included in the
section on Federal Citations, below).
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed. Plans for the recruitment and retention of
subjects will also be evaluated. (See Inclusion Criteria in the sections on
Federal Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to
be used in the project, the five items described under Section f of the PHS
398 research grant application instructions (rev. 5/2001) will be assessed.
ADDITIONAL CONSIDERATIONS
DATA SHARING: The adequacy of the proposed plan to share data.
BUDGET: The reasonableness of the proposed budget and the requested period
of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt: June 19, 2003
Application Receipt: July 17, 2003
Peer Review Date: November/December, 2003
Review by NCAB Advisory Board: February 2004
Earliest Anticipated Start Date: April 01, 2004
AWARD CRITERIA
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.
REQUIRED FEDERAL CITATIONS
HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and
others, and the importance of the knowledge gained or to be gained.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
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,
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
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:
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. 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:
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.
Information concerning essential elements of data safety monitoring plans for
clinical trials funded by the NCI is available:
http://www.cancer.gov/clinical_trials/.
INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of
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 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are
available at https://grants.nih.gov/grants/funding/women_min/guidelines_
amended_10_2001.htm. 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.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:
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
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH
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
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A
continuing education program in the protection of human participants in
research is available online at: http://cme.nci.nih.gov/
HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research
on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).
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.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The
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
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
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.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
Department of Health and Human Services (DHHS) issued final modification to
the "Standards for Privacy of Individually Identifiable Health Information",
the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal
regulation under the Health Insurance Portability and Accountability Act
(HIPAA) of 1996 that governs the protection of individually identifiable
health information, and is administered and enforced by the DHHS Office for
Civil Rights (OCR). Those who must comply with the Privacy Rule (classified
under the Rule as "covered entities") must do so by April 14, 2003 (with the
exception of small health plans which have an extra year to comply).
Decisions about applicability and implementation of the Privacy Rule reside
with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including
a complete Regulation Text and a set of decision tools on "Am I a covered
entity?" Information on the impact of the HIPAA Privacy Rule on NIH
processes involving the review, funding, and progress monitoring of grants,
cooperative agreements, and research contracts can be found at
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
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
http://www.health.gov/healthypeople/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93. 393 (Cancer Cause & Prevention Research
at, http://www.cfda.gov) 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 https://grants.nih.gov/grants/policy/policy.htm
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.