Full Text CA-92-24 BIOLOGY AND IMMUNOLOGY OF BREAST CANCER: AN INTERDISCIPLINARY APPROACH NIH GUIDE, Volume 21, Number 28, August 7, 1992 RFA: CA-92-24 P.T. 34 Keywords: Cancer/Carcinogenesis Immunology Biomedical Research, Multidiscipl National Cancer Institute Letter of Intent Receipt Date: November 3, 1992 Application Receipt Date: December 1, 1992 PURPOSE The intent of this initiative is to encourage interdisciplinary approaches to research on the basic biology and immunobiology of breast cancer. In a recent workshop, a number of areas were identified that would benefit greatly from additional basic research carried out in a multidisciplinary context. These areas include immunology, molecular genetics, endocrinology, and cell biology of breast cancer development. The goal of this Request for Applications (RFA) is to encourage interactive grant applications that propose research with an interdisciplinary approach and that address unanswered questions in the field of breast cancer. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Biology and Immunology of Breast Cancer: An Interdisciplinary Approach, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Research grant applications from interactive groups 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 and local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Interactive Research Project Grant (IRPG) mechanism. Information about this mechanism of support is available in NCI program announcement PA-92-29. The total project period for applications submitted in response to the present RFA may not exceed four years. This RFA is a one-time solicitation. Generally, future unsolicited competing renewal applications as IRPGs or individual R01s will compete with all investigator-initiated R01 applications and be reviewed according to the customary peer review procedures by the Division of Research Grants (DRG). However, should the NCI determine that there is a sufficient continuing program need, a request for renewal applications will be announced. Only recipients of awards under this RFA will be eligible to apply. FUNDS AVAILABLE Approximately $1,500,000 in total costs per year for four years will be committed to fund applications that are submitted in response to this RFA. It is anticipated that at least two IRPG awards will be made, comprising a total of six to eight individual R01 grant awards. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. The earliest start date for the initial award will be July 1, 1993. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Breast cancer is diagnosed in more women per year than any other cancer. One of the major goals of the NCI is to elucidate the biological basis of, and the role of the immune system in, breast cancer. The NCI-sponsored Breast Cancer Research Panel, held in Rockville, Maryland, on April 30 - May 1, 1992, provided a forum for the discussion of current issues and opportunities in breast cancer research. The diverse group of investigators agreed that the breast cancer field would benefit greatly from an interdisciplinary approach. The breast cancer literature has been growing rapidly in so many areas that it has become extremely difficult for an investigator to be knowledgeable in all areas. Research conducted in a collaborative manner will promote development of new insights into this disease because investigators from different disciplines will be able to exchange the most up-to-date information and contribute perspectives and scientific approaches unique for each discipline. The Division of Cancer Biology, Diagnosis, and Centers would like to support basic research in, but not restricted to, the following areas: o Immunobiology - Studies of both positive and negative effects of immune responses on breast cancer development and progression, molecular identification of relevant breast cancer antigens, and the development of effective strategies for immunologically-based prevention or treatment of breast cancer. o Cell Biology - Studies of the organization and differentiation of breast epithelial cells during normal development and progression to malignancy, including studies of interactions between normal and malignant epithelial cells and the surrounding tissue/stroma. o Molecular Genetics - Studies of the contribution of changes in the structure or regulation of oncogenes, tumor suppressor genes, and other important cellular genes to the development and biologic behavior of breast cancer. o Endocrinology (Hormones/Growth Factors) - Studies of the roles of soluble factors and their receptors in breast cancer development and the response to therapy. These may include, but are not limited to, such steroid and nonsteroid factors such as estrogen, progesterone, insulin-like growth factor, prolactin, TGF-ALPHA and TGF-BETA. Although many exciting findings have emerged from basic research in these areas, additional research in an interdisciplinary setting has the potential to provide new insights and enhance the applicability of research findings to clinical problems. The breast cancer literature suggests that these distinct areas of research are interrelated and that progress in understanding breast cancer development requires an understanding of these interrelationships. Three specific examples may be cited from the recent literature. First, it has been shown that the extracellular matrix (ECM) differentially regulates tissue-specific expression of several important genes in breast epithelial cells. This indicates the importance of verifying, in the appropriate experimental systems, conclusions concerning gene expression reached through studies of isolated cells in culture. Long-established tumor cell lines may not be appropriate models for certain kinds of studies because both the genotypes and phenotypes of such cell lines may be different from primary human tumor cells, and because these studies provide little insight to events that occur during the different stages of benign and malignant breast tumors (including early, advanced, remission, and metastasis). Hence, a clinical investigator focused on the elucidation of events that occur during the progression of the disease, a cell biologist focused on the development of appropriate experimental models for breast cancer, and a molecular biologist focused on specific gene expression in different stages or cell types of breast cancer can benefit each other by working closely together. Second, immune system functions can be affected by endocrine factors. For example, there is evidence that the susceptibility of breast cancer cell lines to lysis by lymphokine-activated killer cells is influenced by estrogens. Expression of the lymphokine gamma interferon also appears to be regulated by estrogens. Other cellular components of the immune system are profoundly affected by factors found in the breast environment such as TGF-ALPHA, and neuroendocrine factors such as cortisol and prolactin. This indicates that the development of an effective immune response to breast cancer cells may be as dependent on the hormonal milieu of the tumor and the patient's psychological status as on the presence of suitable antigens as targets. Investigators in the field of immunology, endocrinology, cell biology, and molecular biology can benefit each other when conducting studies to address common questions on the immunobiology of breast cancer. Third, malignant transformation of breast epithelial cells leads to high levels of expression of enzymes that can degrade the intracellular matrix, which may lead to important changes in stromal-epithelial interactions. Enzymologists, cell biologists, and molecular biologists will all be able to contribute to questions concerning involvement of these enzymes in breast cell development. These examples are not meant to indicate special areas of research interest, but merely to illustrate how important it may be to incorporate findings from several fields of research to arrive at conclusions relevant to human breast cancer. The overall goal of this basic research in biology and immunology is to translate these findings into practical clinical applications for early tumor detection and diagnosis, treatment of established tumors, and, ultimately, for prevention intervention in high risk women. However, these clinical and prevention applications are outside the scope of this RFA. SPECIAL REQUIREMENTS Each IRPG must contain at least three individual R01 applications, and address a minimum of two of the major areas of research interest listed in the Research Objectives section of this RFA. Broader diversity of scientific areas is preferred, and although not a requirement, applicants are encouraged to include one or more projects in immunology. One Principal Investigator out of the group must be identified as the "Program Coordinator," and must be cited in all applications on page 2 of form PHS 398. The Program Coordinators of each funded IRPG will be invited to attend the NCI Annual Specialized Program of Research Excellence (SPORE) meeting, a meeting primarily for recipients of the Breast Cancer SPORE Award, to present the progress for the whole project. The IRPG Coordinator must budget funds for the Annual SPORE Meeting. Applicants must describe how their integrated approach will provide a more comprehensive understanding of important problems in breast cancer basic research. Applicants must state clearly how they plan to collaborate. Specifically, they need to address parameters such as sharing of resources and reagents, the planning of the overall scope of the joint project, and the interpretation of experimental outcome. Applicants who already have ongoing collaborations must indicate how their response to this RFA will augment their current collaboration. Because the ultimate goal is to arrive at conclusions relevant to human breast cancer, projects that limit the entire studies to long-established tumor cell lines or animal models must justify the choice of the systems. Although clinical and prevention applications are outside the scope of this RFA, applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator must be included with the application. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder, or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in the Research Plan, parts 1-4, AND summarized in part 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT The designated "Program Coordinator" of each prospective applicant group is asked to submit, by November 3, 1992, a letter of intent that includes descriptive titles of each individual investigator-initiated proposed research project, the names, institutions, addresses, and telephone numbers of the Principal Investigators, 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 is helpful in planning for the review of applications. It allows NCI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Dr. Grace L.C. Shen Cancer Immunology Branch Division of Cancer Biology, Diagnosis, and Centers National Cancer Institute Executive Plaza South, Room 634 6120 Executive Boulevard Rockville, MD 20892-9904 Telephone: (301) 496-7815 FAX: (301) 402-1037 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional business offices and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301/496-7441. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. 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 2a of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, single-sided photocopies, in one package with the appendices to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Referral Officer Review Logistics Branch Division of Extramural Activities National Cancer Institute Westwood Building, Room 848 5333 Westbard Avenue Bethesda, MD 20892-9912 Applications must be received by December 1, 1992. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG 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 by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the program requirements and criteria stated in the RFA is an NCI program staff function. Applications that are judged non-responsive to this RFA will be returned to the applicant by the NCI. Applications judged to be non-responsive to this RFA may be submitted as a component of an unsolicited IRPG, for a traditional research project grant (R01), or for a program project grant (P01) with modification in accordance with either the R01 or P01 guidelines. The application would then not be considered a response to an RFA. If the number of applications submitted is large compared to the number of awards to be made, the NCI may conduct a preliminary scientific peer review (triage) to eliminate those that are clearly not competitive. The NCI will remove from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and institutional official. Those applications judged to be both responsive and competitive will be further evaluated according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NCI. The second level of review will be by the National Cancer Advisory Board. Review criteria for this RFA will be: o extent to which the proposed research addresses the goals of the RFA o scientific, technical, or medical significance and originality of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o where applicable, appropriateness of the model system chosen for the experiments proposed and potential relevance of the model system to human breast cancer o demonstrated expertise in both the appropriate basic and clinical sciences of the PI and key personnel, particularly but not exclusively in the area of the proposed research o demonstration of availability and access to appropriate resources necessary to perform the research o where applicable, availability of clinical information associated with human samples o adequacy of provision for the protection of human subjects and the humane treatment of animals o adequacy of the plans for inclusion of females and minorities o adequacy of available facilities The reviewers will also judge the appropriateness of the proposed budget and duration in relation to the proposed research. For each application that is given a priority score, the review group will assign an adjectival descriptor that reflects the extent and effectiveness of its collaboration(s) with other applications included in the IRPG. This assessment will be documented in a brief administrative note in the summary statement to assist the NCI in making final decisions on each application in the context of the overall IRPG. AWARD CRITERIA The anticipated date of award is July 1, 1993. In addition to technical merit of the application, the NCI will consider how well the proposed research meets the goals and objectives of the program as described in the RFA, as well as the level of total cost requested. Only highly-rated projects will be funded. The intention is to support IRPGs consisting of at least three high quality projects. However, for programmatic reasons, as few as two projects of an IRPG may be funded. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged and should be directed to the program director listed below. NCI program staff welcome the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Dr. Grace L.C. Shen Cancer Immunology Branch Division of Cancer Biology, Diagnosis, and Centers National Cancer Institute Executive Plaza South, Room 634 6120 Executive Boulevard Rockville, MD 20892-9904 Telephone: (301) 496-7815 FAX: (301) 402-1037 Direct inquiries regarding fiscal matters to: Mr. Robert Hawkins Grants Management Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800, ext. 13 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.396. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .

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