CHEMOPREVENTION OF ESTROGEN RECEPTOR (ER) NEGATIVE BREAST CANCER PRECLINICAL STUDIES Release Date: March 21, 2002 RFA: CA-03-005 National Cancer Institute (NCI) (http://www.nci.nih.gov/) LETTER OF INTENT RECEIPT DATE: June 27, 2002 APPLICATION RECEIPT DATE: July 25, 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 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 The initiative will encourage applications focused on 1) validation of surrogate biomarkers, which can be modulated by agents which may prevent Estrogen Receptor (ER) negative breast cancer in animal models of non- hormonally responsive mammary cancer. The experimental protocols in animals should parallel potential clinical chemoprevention protocols for breast cancer in humans, 2) identification of potential targets found both in hormonally non-responsive animal models of breast cancer and in ER negative breast cancer in humans and 3) determination of the efficacy of potential chemopreventive agents. Modulatable surrogate biomarkers are broadly defined and might include gene or protein expression, specific DNA mutations or chromosomal alterations or characteristics associated with imaging (e.g. breast density, nuclear morphometry, etc.) which can be quantitatively altered by an effective chemopreventive agent. Modulatable surrogate biomarkers could be examined in lesions (preinvasive lesions, invasive lesions), in at risk epithelium or in serum. One should be able to demonstrate a strong correlation between alteration of the biomarker and the effects of the chemopreventive agent on tumor incidence and multiplicity in the animal model. 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 cancer (e.g., tamoxifen , raloxifene, retinoids, COX-2 inhibitors). Animal models aimed at developing new, specific and potentially potent agents for prevention of ER negative breast cancer as well as potentially offering modulatable biomarkers should accelerate and drive forward the clinical research on ER negative breast cancer. These developments should help to diminish the risk of ER negative breast cancer and, in conjunction with agents which are effective against ER positive breast cancer (tamoxifen, raloxifene, aromatase inhibitors) , offer the possibility of regimens which will profoundly decrease the overall risk of breast cancer. The American Cancer Society estimates that in this year 193,000 new cases of breast cancer will be diagnosed and that roughly 40,000 women will die of this disease. It is estimated that roughly 30% of breast cancers are ER negative and that they represent 12-15,000 of the breast cancer related deaths each year. Short term pilot (Phase II) clinical studies in women at risk of developing ER negative breast cancer represent an efficient way of demonstrating potential efficacy of preventive agents. These studies depend heavily on the development of potential agents and cancer-related surrogate endpoints employing animal models. Such endpoints might include: levels of expression of specific genes or proteins, incidence or levels of specific genetic alterations (LOH, microsatellite alterations, FISH, mutations in suppressor/oncogenes, base methylation in certain genes), and or parameters related to image analysis, (e.g., nuclear morphometry , breast density, etc.). Such endpoints could be determined in lesions, in epithelial cells at high risk of developing cancer or in serum. These surrogate markers can be validated in animal studies where experiments can be followed till the production of invasive tumors. Surrogate endpoints that have already undergone some studies in animal models for breast cancer include expression of various genes, proliferation, apoptosis, and nuclear imaging. The incorporation of newer imaging technology into small animal cancer prevention assays to validate their future use in clinical trials protocols is also encouraged. However it is clear that a larger effort is needed to validate surrogate endpoint biomarkers in preclinical models employing intermediate endpoints similar to those proposed clinically for women at high risk of ER negative tumors. Once validated in animal models with a cancer endpoint, these biomarkers could then be rapidly translated into the clinical trials effort. In developing these endpoint biomarkers, the use of classes of agents which appear to be promising for ER negative breast cancer (e.g. COX-2 inhibitors, EGFr inhibitors, RXR agonists , farnesyltransferase inhibitors, etc.) might be prime candidates. Biomarkers developed for these drugs could be immediately translated to clinical trials. In contrast markers developed for totally new agents will require significant toxicologic and pharmacologic testing of those new agents prior to their use in clinical trials. Further studies with several potential classes of agents warrant further evaluation in relevant preclinical animal models before they can be nominated for preventive interventions in the population of women at risk for ER negative disease. For example, members of the non-steroidal anti-inflammatory drug family (NSAIDs) have shown some efficacy in hormonally responsive models of breast cancer and their primary target COX-2 is expressed in ER negative tumors as well. Therefore, further investigations of this class of agents in ER negative models appears appropriate. Based on preclinical animal studies and limited human studies, other potential agents to consider, include inhibitors of Neu and EGFr, rexenoids, farnesyl transferase inhibitors , etc. While these are examples, additional agents based on specific targeting to ER negative tumors are encouraged for testing in these applications. One might hope that additional targets might be defined by examining genes or proteins whose expression is altered in ER negative breast cancer. Thus EGFr and Neu have been identified as potential targets. However, the continued cataloging of gene and protein expression changes by RNA or proteomic approaches is likely to result in many additional targets. Combination prevention trials targeting specific biochemical pathways may also have great potential for leading to more effective preventive strategies based on multiple mechanistic approaches. Thus the combination of an antiestrogen/estrogen plus a rexenoid appears to have synergistic effects in ER positive breast cancer models in animals. Objectives and Scope: The development of animal model protocols that can facilitate the discovery and development of agents to prevent or diminish the risk of ER negative breast cancer in women represents an extraordinary opportunity to reduce breast cancer incidence, morbidity, and mortality. The purpose of this initiative is to invite investigator-initiated grant applications developing and evaluating chemopreventive strategies preclinically which could be rapidly translated to clinical studies and are applicable to women at high risk for development of ER negative breast cancer. The range of activities supported by this RFA would include preclinical studies to: 1) develop modulatable endpoint biomarkers in animal models of hormonally non responsive breast cancer employing effective preventive agents. Such biomarkers might include: gene or protein expression, or specific molecular changes, DNA mutations, image analysis etc. in specific preclinical models in which relevant cancer incidence and multiplicity are decreased by known effective agents. Interventions and determinations of endpoints that parallel potential clinical protocols are of particular use. Thus clinical protocols are likely to examine preinvasive lesions, at risk epithelia or sera in addition to more advanced lesions for modulation of potential endpoints. However a portion of any protocol would be to carry animals to an invasive tumor endpoint to determine the correlation of marker modulation and the final tumor endpoint. 2) test and prioritize agents using preclinical animal models for ER negative breast cancer. It would be expected that >40% of the animals would develop hormonally non responsive mammary tumors in any model that is proposed. In addition the model should develop preinvasive and invasive lesions that are histologically similar to that observed in human breast cancer. The purpose of this RFA is not primarily to support development of totally new animal models for ER negative breast cancer. However, a grant which includes as a component limited alteration or optimization or prevention testing in a previously developed model is not precluded. If one employs a transgenic animal model one must determine whether a given chemopreventive agent affects expression of the promoter. 3) Further characterize by genomic, proteomic or imaging techniques changes associated with hormonally non responsive breast cancer in multiple animal models as well as correlating with those seen in lesions or serum of humans with ER negative breast cancer or individuals at high risk of developing, ER negative breast cancer. In order to facilitate these comparative studies NCI will supply grantees funded via this RFA with a limited number of animal tumors, normal tissue and serum samples from 3 different hormonally non responsive tumor models. The specific models may be from rats or mice and will depend on availability. NCI will not supply rodents for the primary chemopreventive studies. Applicants are especially encouraged to apply chemopreventive agents directed against certain of the recently identified molecular targets found in ER negative breast cancer in humans (e.g. Neu, EGFr, COX-2) . Although it is anticipated that any model would have been characterized for the presence of histopathologic lesions it would be useful to do some early characterization of any models for gene expression patterns and expression of targets that are similar to that observed in humans. Approaches comparing any animal results to known results in humans. For example, the published published results of Perou, et al (Nature 406, 747-752 or results from the CGAP web site (http://cgap.nci.nih.gov/) etc., can be employed. Based on these initial characterizations the applicant should identify potential markers, e.g., genes or gene products which are over expressed or under expressed in hormonally non responsive mammary lesions in their model. The investigators funded under this RFA will be encouraged to collaborate with scientists involved in the Mouse Models for Human Cancer Consortia (MMHCC) and take advantage of animal models developed in the MMHCC. Transgenic animal models for mammary cancer are already under development and might be used with the application of drug development. Similarly newly developed imaging techniques that as are being evaluated as part of the MMHCC activities could be incorporated. The total project period for applications submitted in response to the present RFA may not exceed 5 years. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the duration and sizes of awards will vary also. Therefore applications will be accepted for R01, R21/R33, and competitive supplements to existing awards in this area. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April 2003. This RFA uses just-in-time concepts. It also uses the modular and 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 The NCI intends to commit approximately $3.0 million in FY 2003 to fund 7 to 10 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $300,000 per year. Facility and Administrative costs on consortium arrangements are not included in direct cost requests greater than $250,000. 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. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. 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. The NIH Grants Policy Statement governs the research grant programs awarded under this RFA. Awards under this RFA to foreign institutions will be made only in accordance with NIH policy governing such awards. SPECIAL REQUIREMENTS In order to facilitate discussion and cooperation between investigators funded under this RFA two meetings among the various investigators funded by this RFA will be held. The first meeting would take place within two months of initial funding and the second meeting would be undertaken approximately 24 months later. Therefore, it is a requirement that investigators include the costs of these two one day meetings in their submitted budgets. An investigator should address the following questions: 1. Does your study include examination of tissues e.g. at risk epithelia, preinvasive lesions and sera which are likely to be obtained in clinical cancer prevention trials? 2. Does your investigation include some agents with known efficacy in the proposed or similar models? 3. Are any technical approaches and techniques proposed likely to be directly applicable to clinical cancer chemoprevention trials? 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. Ronald Lubet Division of Cancer Prevention Institute or Center, MSC 7322 Executive Plaza North, 2110 Bethesda, MD 20892 Telephone: (301) 594-0457 FAX: (301)402-0553 Email: rl57q@nih.gov o Direct your questions about 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: ncidearefof-r@mail.nih.gov o Direct your questions about financial or grants management 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 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. Ronald Lubet Division of Cancer Prevention Institute or Center, MSC 7322 Executive Plaza North, 2110 Bethesda, MD 20892 Telephone: (301) 594-0457 FAX: (301)402-0553 Email: rl57q@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) at 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. 5/2001) 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: https://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 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 Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 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 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 for responsiveness by the NCI program staff. 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 an important problem? 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? Does your study address the development of agents and or surrogate biomarkers applicable to estrogen receptor negative breast cancer? Does your study include examination of tissues e.g. at risk epithelia, preinvasive lesions, sera which are most likely to be obtained in clinical cancer prevention studies? Do you propose the use of at least some agents with known efficacy in the proposed or similar models? It will be difficult to optimize markers with minimally effective agents. (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? Are the approaches employed directly applicable to cancer chemoprevention trials? Are any technical approaches directly applicable to clinical cancer chemoprevention trials? (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. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) 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 27, 2002 Application Receipt: July 25, 2002 Peer Review Date: November/December 2002 Review by NCAB Advisory Board: February 2003 Earliest Anticipated Start Date: April 2003 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 as it relates specifically to this RFA. 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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA 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. Reviewers are cautioned 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, CHEMOPREVENTION OF ESTROGEN RECEPTOR (ER) NEGATIVE BREAST CANCER :PRECLINICAL STUDIES, is related to priority area of Cancer: Reduce the number of new cancer cases as well as the illness, disability, and death caused by cancer. 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. 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 (https://grants.nih.gov/grants/policy/policy.htm). 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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