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 301/710-0267, 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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