CHEMOPREVENTION OF TOBACCO-RELATED CANCERS IN FORMER SMOKERS:  
PRECLINICAL STUDIES

RELEASE DATE:  February 12, 2002

RFA:  RFA-CA-03-004

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)

Letter of Intent Receipt Date:  June 21, 2002
Application Receipt Date:       July 26, 2002

This RFA is a reissue of RFA-CA-02-008, which was published in the NIH Guide 
on 04/20/2001.

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 Special Requirements
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:

New extraordinary opportunities are defined annually in the National Cancer 
Institute"s Annual By-Pass Budget. One of the extraordinary opportunities for 
several years has been the field of tobacco research. As part of the 
implementation plan to address this opportunity, the Division of Cancer 
Prevention, NCI, invites applications for new R01 and R21 grants and 
competitive supplements to existing grants to apply protocols which mimic the 
former smoker condition to preclinical animal models. Such research should be 
focused on (1) validating surrogate biomarkers for tobacco-related cancers in 
animal models under experimental protocols that mimic the high risk of former 
smokers and (2) identifying and prioritizing agents that prevent cancers in 
tobacco-susceptible organ systems using protocols which mimic the higher risk 
of former smokers at the time of intervention.

Another related RFA is anticipated that will invite applications for clinical 
research projects of similar objectives using the Cooperative Agreement 
(U01) mechanism.  
See: http://deainfo.nci.nih.gov/concepts/chemo_tobac_relatedclin.htm.

RESEARCH OBJECTIVES  

Preclinical studies using animal models have been critically important for 
identifying a number of chemical agents which are now being applied in the 
prevention of tobacco-related cancers (e.g., glucocorticoids, retinoids, COX-2 
inhibitors, farnesyl transferase inhibitors).  Further use of animal models 
with unique protocols aimed at developing newer more potent agents for 
prevention of tobacco-related cancers may accelerate the clinical research in 
this field.  These developments will diminish the risk of tobacco -related 
cancers.   This RFA is designed to support research projects that examine 
agents for chemopreventive activity in cancers related to former smokers and 
address the development, validation and application of surrogate biomarkers 
for these agents. Prevention studies should employ late intervention protocols 
that mimic the risk and are applicable to former smokers. The target organs of 
interest include lung, head and neck, bladder, esophagus, pancreas, cervix, 
and colon. The goals of these studies are to provide agents and surrogate 
markers for future clinical trials to prevent cancers in former smokers.
 
Scope and Objectives
 
Clinical studies depend heavily on the development of cancer-related surrogate 
endpoints. Preclinical studies using former smoker protocols, examining the 
effect of interventional agents on molecular endpoints and imaging, represent 
an efficient way of developing and validating such surrogate endpoints. These 
endpoints might include: levels of expression of specific genes or proteins 
associated with cancer, incidence or levels of specific genetic alterations 
(loss of heterozygosity (LOH), microsatellite alterations, fluorescent in situ 
hybridization (FISH), mutations in suppressor/oncogenes, base methylation in 
certain genes), and image analysis of preneoplastic lesions at high risk for 
progression to overt cancer.  There are several surrogate markers already 
being validated preclinically for lung, bladder, esophagus and other tobacco-
related cancers, including: DNA adducts, proliferating cell nuclear antigen 
(PCNA), LOH and FISH analysis, nuclear imaging, and apoptosis.  The 
incorporation of newer imaging technology, such as spiral CT, PET, MRI, or 
combinations, into small animal cancer prevention assays to validate their 
future use in clinical trial protocols is also encouraged. Once these 
surrogate endpoints are validated in animal studies, they could then be 
rapidly translated into the clinical trial effort.

Several potential agents warrant further evaluation in relevant preclinical 
animal models before they can be nominated for preventive interventions in the 
population of former smokers. For example, members of the non-steroid anti-
inflammatory drug family (NSAIDs) have shown efficacy in animal models for 
multiple tobacco-related malignancies including cancers of the bladder, lung, 
upper aerodigestive tract, and esophagus.  Based on pre-clinical animal 
studies and limited human studies, other potential agents to consider, 
especially for lung and upper aerodigestive tract, include glucocorticoids, 
lipoxygenase inhibitors, farnesyl transferase inhibitors, epithelial growth 
factor receptor (EGFr) inhibitors, selenium, and myo-inositol. While these are 
examples, newer agents are encouraged for testing in these applications. 
Combination prevention trials targeting specific biochemical pathways based on 
multiple mechanistic approaches also have great potential for leading to more 
effective preventive strategies.  Specifically, Celecoxib, a highly specific 
cyclooxygenase-2 (COX-2) inhibitor with minimal toxicity, has already been 
shown to be effective for prevention of colon adenomas in Familial Adenomatous 
Polyposis (FAP) patients. Elevated COX-2 levels are known to occur in a 
variety of neoplasms, including non-small cell lung cancer (NSCLC), esophagus, 
and bladder. Additionally, there are preclinical data supporting the use of 
lipoxygenase inhibitors in various organs. Therefore a combination of a COX-2 
inhibitor with a lipoxygenase inhibitor may prove efficacious by blocking both 
major arms of the arachidonic acid metabolic pathway. Alternatively, the use 
of a COX-2 inhibitor in combination with a farnesyl transferase inhibitor 
might also be considered as a promising approach for a larger clinical study 
in former smokers.   Based on better understanding of the regulatory 
mechanisms involved in tumor development and progression, various new agents 
could be discovered, which could have a profound effect on the incidence of 
tobacco-related cancers. Animal models, which parallel clinical trials with 
former smoker exposure protocols, will be critically important to test known 
promising agents and to screen new mechanistic classes of agents. Animal 
carcinogenesis models (transgenic, carcinogen-induced, tobacco-exposed, or 
combinations thereof) which develop pathological and genetic expression 
changes similar to human cancers should be proposed. These models (with 
intervention protocols similar to that in former smokers) should identify 
agents that act during the progression stage of cancer. The overall 
effectiveness of the model would be to correlate changes in surrogate 
endpoints with the ability of that intervention to inhibit invasive cancer. 
The use of relatively effective chemopreventive agents is important since 
examination of surrogate endpoint modulation is key to validation. 

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01), exploratory/developmental grants (R21), and competing supplements 
to existing R01 grants mechanisms.  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed project. The 
total project period for an R01 application submitted in response to this RFA 
may not exceed 3 years.  For an R21 application, support may not exceed 2 
years.  For a competing supplement to a grant, a minimum of 2 years should 
remain in the parent grant from the time of submission. 

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats 
(see http://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  

The NCI intends to commit approximately $3.0 million in FY 2003 to fund 6 to 8 
new and/or competitive supplement grants in response to this RFA.  For R01s an 
applicant may request a project period of up to 3 years and a budget for 
direct costs of up to $500,000 per year. Applications with requested budgets 
up to $250,000 must use the modular grants format.  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.  Applicants for the R21 grant mechanisms 
may request up to $100,000 direct costs (four budget modules) per year unless 
the application includes consortium costs, in which case the limit is $125,000 
direct costs (five budget modules) per year.  Support may not exceed two years.   

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
 
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. 

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 will be administered under NIH grants policy as stated in 
the NIH Grants Policy Statement, March 2001, available on the internet only at 
http://grants.nih.gov/grants/policy/nihgps_2001/.

SPECIAL REQUIREMENTS

The application should discuss potential patent coverage and intellectual 
property rights which may result from this research. Since the discovery of 
new surrogate endpoints and new chemopreventive agents as related to the 
former smoker problem is the objective of this research effort, the sharing of 
intellectual property by the applicant institution with the NCI for further 
clinical development is essential to any and all awards made under this RFA. 

Applicants proposing to access the Chemoprevention Repository of the NCI for 
agents must obtain written permission from the Chemoprevention Agent 
Development Research Group (CADRG) http://cancer.gov/prevention/cadrg. 
A signed letter from the CADRG stating that it will provide the amount of 
agent needed for the complete study is required at the time of submission of 
the application.

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:

Direct your questions about scientific/research issues to:

Vernon E. Steele, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Blvd., Room 2108, MSC-7322
Rockville, MD  20852 (express courier)
Bethesda, MD  20892-732 (mail)
Phone:  (301) 594-0420 
FAX:  (301) 402-0553
Email:  [email protected]

Direct inquiries regarding review issues to:

Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8041, MSC-8326
Rockville, MD  20852 (express courier)
Bethesda MD  20892-8326 (mail)
Telephone:  (301) 496-3428
Fax:  (301) 402-0275
Email:  [email protected]

Direct your questions about financial or grants management matters to:
 
Eileen Natoli
Grants Administration Branch
National Cancer Institute
EPS, Room 243
Rockville, MD  20852 (express courier)
Bethesda, MD  20892 (mail)
Telephone:  (301)  496-8791 
FAX:  (301) 496-8601
Email:  [email protected]

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 subsequent applications, the information that it 
contains allows NIH staff to estimate the potential review workload and to 
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:

Vernon E. Steele, Ph.D., M.P.H.
Division of Cancer Prevention
National Cancer Institute 
EPN Room 2108, MSC 7322
Rockville, MD  20852 (express courier)
Bethesda, MD  20892-7322 (mail)
Telephone:  (301) 594-0420
FAX:  (301) 402-0553 
Email:  [email protected]

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 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact Grants Information, Telephone (301) 
710-0267, Email:  [email protected].

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) at 
http://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 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
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:  
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710 (mail)
Bethesda, MD  20817 (express/courier)
 
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 Blvd., Room 8041, MSC-8329
Rockville, MD  20852 (express courier)
Bethesda MD  20892-8329 (mail)

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.) 
(http://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 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.
 
APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  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.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NCI.

Incomplete applications will be returned to the applicant without further 
consideration.  And, if the application is not responsive to the RFA, CSR 
staff may contact the applicant to determine whether to return the application 
to the applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

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
o Receive a second level review by the National Cancer Advisory Board. 
 
REVIEW CRITERIA

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

(1) SIGNIFICANCE:  Does your study address the development of chemopreventive 
agents and surrogate biomarkers for former smokers? If the aims of your 
application are achieved, how do they advance scientific knowledge?  What will 
be the effect of these studies on the concepts or methods that drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider 
alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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:

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.

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 Date:    June 21, 2002
Application Receipt Date:         July 26,2002
Peer Review Date:                 November/December, 2002
Council Review:                   February, 2003
Earliest Anticipated Start Date:  April, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

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 
http://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.

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,  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 http://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.

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