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

Release Date:  April 19, 2001

RFA:  RFA-CA-02-008

National Cancer Institute

Letter of Intent Receipt Date:  June 25, 2001
Application Receipt Date:       July 30, 2001

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
 
PURPOSE

New extraordinary opportunities are defined annually in the National Cancer 
Institute’s Annual By-Pass Budget. One of the extraordinary opportunities is 
in 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 organ systems of 
tobacco-related cancers 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/recentcleared.htm.

RESEARCH OBJECTIVES  

Background

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, which 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 
(LOH, microsatellite alterations, 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, PCNA, 
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, 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 also have great potential for leading 
to more effective preventive strategies based on multiple mechanistic 
approaches.  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. 

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). 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.

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.  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  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 grant a minimum of 2 years 
should remain in the parent grant. Because the nature and scope of the 
research proposed in response to this RFA may vary, it is anticipated that the 
size of awards and supplements will vary, but the supplements are 
nonrenewable. Continuation of projects developed under this program must be 
renewed through other mechanisms. The earliest anticipated award date is April 
1, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.  

FUNDS AVAILABLE  

The NCI intends to commit approximately $3,000,000 in FY 2002 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.  Because the nature and 
scope of the research proposed may vary, it is anticipated that the size 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.  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.   

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State or local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators.

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/.  

INQUIRIES
  
Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic 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
Phone: (301)594-0420 
FAX: (301)402-0553
Email: vs1y@nih.gov

Direct inquiries regarding review issues to:

Ms. Toby Friedberg 
Referral Officer 
Division of Extramural Activities 
National Cancer Institute 
6116 Executive Blvd., Room 8109, MSC-8326
Rockville, MD 20852 (express courier)
Bethesda MD 20892-8326
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: tf12w@nih.gov

Direct inquiries regarding fiscal matters to:
 
Eileen Natoli
Grants Administration Branch
National Cancer Institute
EPS, Room 243
Bethesda, MD  20892
Telephone: (301)  496-8791 
FAX: (301) 496-8601
Email: natolie@gab.nci.nih.gov

LETTER OF INTENT  

Prospective applicants are asked to submit, by June 25, 2001, a Letter of 
Intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted.  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 to Dr. Vernon Steele listed under INQUIRIES 
by the Letter of Intent receipt date.

SCHEDULE

Letter of Intent Receipt:         June 25, 2001
Application Receipt:              July 30, 2001
Peer Review Date:                 October/November 2001
Review by NCAB Advisory Board:    February, 2002
Earliest Anticipated Start Date:  April, 2002

APPLICATION PROCEDURES  

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.  
Applications kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
grantsinfo@nih.gov.  For those applicants with internet access, the 398 kit 
may be found at: http://grants.nih.gov/grants/funding/phs398/phs398.html

Applicants are strongly encouraged to call the program contacts listed in 
INQUIRIES with any questions regarding the responsiveness of their proposed 
project to the goals of this RFA. 

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year for R01, and up to a total 
direct cost request of $100,00 per year ($125,000 if there are 
consortium/contractual costs) for R21.  (Applications that request more than 
$250,000 direct costs for an R01 in any year must follow the traditional PHS 
398 application instructions.)  The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus Facilities and Administrative (F&A) costs] for the initial 
budget period.  Items 8a and 8b should be completed indicating the Direct and 
Total Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION -  Prepare a Modular Grant Budget Narrative 
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages).  At the top of the page, enter the total direct costs requested for 
each year.  This is not a form page.

o  Under Personnel, list all project personnel, including their names, percent 
of effort, and roles on the project.  No individual salary information should 
be provided.  However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the nearest 
$1,000.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of all personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is domestic or foreign.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount.  
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three pages 
may be used for each person.  A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research
projects ongoing or completed during the last three years; and
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST -  This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

Applications not conforming to these guidelines will be considered 
unresponsive to this RFA and will be returned without further review.

FOR ALL APPLICATIONS

The RFA label available in the PHS 398 (rev. 4/98) 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 sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

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:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8326
Bethesda, MD  20892-8326
Rockville, MD  20852 (for express/courier service)

Applications must be received by July 30, 2001.  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.  

REVIEW CONSIDERATIONS

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 of the National Cancer Institute in 
accordance with the review criteria stated below.  As part of the initial 
merit review, all applications will receive a written critique and undergo a 
process in which only those applications deemed to have the highest scientific 
merit, generally the top half of the applications under review, will be 
discussed and assigned a priority score. These scored applications will 
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.  The 
specific goals of this RFA are to (1) validate surrogate endpoints for the 
cancer process in tobacco-related target organs using known chemopreventive 
agents, and (2) identify and prioritize agents that lower the cancer risk 
using animal models and protocols which mimic the former smoker condition. 
Supplemental funds may be requested to add a new protocol mimicking the former 
smoker scenario to an existing study. Meritorious projects will include 
imaginative intervention agents and insightful endpoint validation approaches, 
which will reveal agents and endpoints immediately translatable to the 
clinical setting.

The reviewers will comment on the following aspects of the application in 
their written critiques in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered by the reviewers in 
assigning the overall score weighting them as appropriate for each 
application.  Note that the 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, an investigator 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 the reduction of risk in former smokers?  
If the aims of the application are achieved, will the data produce new 
validated surrogate endpoints or new agents to be advanced into clinical 
trials?  What will be the effect of these studies have on future development 
of new compounds and surrogate endpoints for future clinical interventions?  

Approach: Are the conceptual framework, design, methods, and analyzes 
adequately developed, well integrated, and appropriate to the former smoker 
problem?  Are the experimental protocols directly applicable to the former 
smoker risk and timing of the intervention? Does the applicant acknowledge 
potential problem areas and consider alternative tactics?  If screening is 
proposed, are data handling procedures adequate, and are the criteria for a 
valid assay proposed? How will the data be statistically analyzed? What is the 
method by which the agents are prioritized for future development?

Innovation: Does the project employ novel concepts, approaches, or methods?  
Does the project challenge existing paradigms or develop new methodologies or 
technologies?  Are the protocols and interventions novel and unique?

Investigator: Is the investigator appropriately trained and experienced 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 ? 

The initial review group will also examine the appropriateness of proposed 
project budget and duration. 

Additional scientific/technical merit criteria specific to the objectives of 
the RFA:

The surrogate endpoints developed and validated and the agents tested and 
prioritized should be readily translatable to the clinical trial setting in 
former smokers. 

AWARD CRITERIA
 
Applications recommended by the National Cancer Advisory Board will be 
considered for award based upon (a) scientific and technical merit; (b) 
program balance, including in this instance, sufficient compatibility of 
features to make a successful collaborative program a reasonable likelihood; 
and (c)  availability of funds. 

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.393, (for Cancer Cause and Prevention Research).  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 and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products.  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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