Full Text CA-92-07 DOMESTIC ANIMAL MODELS FOR RETROVIRUS-ASSOCIATED HUMAN CANCERS RFA: CA-92-07 P.T. 34 Keywords: Disease Model Etiology Viral Studies (Virology) Cancer/Carcinogenesis Antivirals National Cancer Institute Letter of Intent Receipt Date: February 28, 1992 Application Receipt Date: April 28, 1992 PURPOSE Retroviruses isolated from mammalian species have the potential to provide valuable basic information on the etiology and mechanism(s) of cancer induction by viruses and to serve as models for evaluating antiviral agents prior to human clinical trials. The occurrence of neoplastic sequelae in retrovirus-infected animals supports the view that these viruses may be directly or indirectly involved in the etiology of malignancies. The identification and development of suitable animal models of viral neoplasia may aid in investigations of the mechanisms of cancer initiation and progression, ultimately providing a better understanding of the role of viruses in the etiology of human cancer. The Congress, in both FY 90 and FY 92, has expressed its interest in retroviral infections in large domestic animals as excellent models for retroviral-induced diseases in humans such as leukemia, lymphosarcoma, and AIDS. 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 Request for Applications (RFA), Domestic Animal Models for Retrovirus- Associated Human Cancers, is related to the priority area of cancer etiology. 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 Non-profit and for-profit, domestic and foreign, organizations and institutions, governments and their agencies are eligible to apply. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) individual research grant, R01. Applicants will be responsible for the planning, direction, and execution of the proposed project. In addition to traditional R01 grants, investigators may submit applications for collaborative efforts using the Interactive Research Project Grant (IRPG), which was recently announced by the NCI (PA-92-29) in the NIH Guide for Grants and Contracts (Vol. 21, No. 1, 01/10/92). Potential applicants interested in the interactive project approach should consult that program announcement for specific guidance. A minimum of three independent investigators with related research objectives may submit concurrent but independent R01 grant applications that share a common focus. Each application that is part of an IRPG package will be considered on its own merit as an individual research project. Therefore, applicants for IRPGs MAY NOT concurrently submit R01 applications that represent significant duplication of efforts described in the applicant's IRPG. In this regard, it should be noted that the National Cancer Institute (NCI) will consider funding meritorious individual IRPG applications if it is not possible to fund the IRPG package as a whole. Except as otherwise stated in this RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. This RFA is a one-time solicitation. Future unsolicited competitive continuation applications will compete with all other investigator-initiated applications and be reviewed by the Division of Research Grants (DRG). If the NCI determine that there is a sufficient continuing program need, a request for competitive continuation applications will be announced. Only recipients of awards under this RFA will be eligible to apply. FUNDS AVAILABLE Approximately $1,750,000 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 five to seven awards will be made. The level of funding is dependent on the receipt of a sufficient number of applications of high scientific merit. The total project period for applications submitted in response to the present RFA may not exceed four years. The earliest feasible start date for the initial awards will be September 1992. Although this program is provided for in the financial plans of the NCI, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Progress in the development of models of viral-associated malignancies of large domesticated animals has been hampered due to the indolent nature of the disease course, the limited number of livestock animals that develop malignancies, and the diversity of viruses that can induce neoplasia or play a role as an etiologic co-factor. In order to address these issues in a systematic and timely way and in response to earlier Congressional interest in basic research on retroviruses of large domesticated animals, a workshop entitled "Animal Models of Retrovirus-Associated Malignancies" was convened by the Biological Carcinogenesis Branch, Division of Cancer Etiology (DCE), NCI, on November 15, 1990. The purpose of the workshop was to assess the current state of knowledge of retroviral infections in animals, the etiology of neoplasms in domestic animals, and the areas of research that might require stimulation or resources for continued progress. The neoplastic potential of various retroviruses and the different molecular mechanisms by which viruses might be involved in the neoplastic processes have yet to be fully enumerated. Retroviruses can transcriptionally activate host genes by cis- or trans-mechanisms or inactivate host genes by direct insertional disruption. In the avian and rodent system, retroviral insertional activation (and, in one case, inactivation) of cellular oncogenes represents a key step in oncogenesis caused by nonacute retroviruses that do not carry their own oncogenes. A by-product of this process is the genesis of oncogene-transducing retroviruses. Little is known about the ability of the host to restrict the replication of retroviruses, and thus it is not known which host factors determine whether a virus replicates lytically or might be involved in the initiation or progression of neoplastic sequelae. Some retroviruses, such as the equine infectious anemia virus in horses, have not been shown to be involved in malignant sequelae, while other retroviruses, such as the feline leukemia viruses, are frequently involved in malignancies. Studies on the pathogenesis of cancers of viral origin from animal models should result in new knowledge relevant to human cancer. This RFA focuses on the retroviruses of domestic livestock because unique virus models have been identified that display correlative aspects to human neoplasia. For example, bovine leukemia virus, the causative agent of lymphosarcomas in cattle, is closely related to HTLV-1, the etiologic agent of adult T-cell leukemia in humans; ovine pulmonary carcinoma is a naturally occurring retrovirus- associated pulmonary neoplasm of mature sheep; a nasal carcinoma in sheep has recently been etiologically linked to a type D retrovirus infection; and the bovine papillomavirus induces esophageal, ocular, and skin carcinomas in the cow that are related to human papillomavirus-induced malignancies. Research Goals and Scope Progress in research on retroviruses of domestic livestock models has been limited by the indolent course of the disease and the fact that the neoplasms may occur in a limited percentage of animals. Other limitations include the difficulty in propagating the viruses in tissue culture systems, a lack of reagents for typing of cells of the animal's immune system, nucleic acid probes for some viruses are either not available or are not well characterized, and monoclonal antibodies for some viral antigens and host cell proteins with which the viruses interact are not available. Additionally, only a small number of scientists are actively conducting research on each virus. One goal of this RFA is to encourage collaborations between scientists with complementary areas of research expertise, such as molecular biology of retroviruses and pathogenesis or immunology, with the intent of accelerating progress in these important cancer models. The overall purpose of the RFA is to help stimulate research activity in these retrovirus cancer models and overcome these limitations. The objectives of the RFA are to encourage basic research on retroviral pathogenesis in domestic livestock animals. These studies will aid in the understanding of the properties of viruses and features of the host and its response that determine disease progression from initial virus infection to neoplastic sequelae. For the purposes of this RFA, domestic animals include cows, horses, sheep, goats, and pigs; specifically excluded are retroviruses of dogs, cats, primates and avian species. Collaborative efforts between scientists with complementary areas of research expertise will be encouraged. The areas of proposed investigation include: (1) investigations of the oncogenic mechanisms in domestic livestock retroviruses; (2) investigation of cancer etiology and viral pathogenesis from initial infection through the development of pre-neoplastic lesions and neoplastic sequelae with retroviruses of domestic livestock; (3) the role of RNA and DNA viral co-factors in cancer etiology animal models and definition of virus- and co-factor-host interactions and immune function alterations in the host that dispose the host to neoplastic processes; (4) investigations to assess the role of the host immune system and host genetic factors in the control and limitation of virus replication, and the susceptibility or resistance of animals to oncogenic processes; and (5) studies on the expression and regulation of viral and/or associated host cell genes in pre-neoplastic lesions and malignant tissues from retrovirus-infected domestic livestock animals. LETTER OF INTENT Prospective applicants are asked to submit, by February 28, 1992, a letter of intent that includes a descriptive title of the proposed research, the name and address of the Principal Investigator, the names of other key personnel, the participating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, it is requested in order to provide an indication of the number and scope of applications to be reviewed. It also 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. Kenneth J. Cremer Program Director, AIDS Virus Studies Biological Carcinogenesis Branch Division of Cancer Etiology National Cancer Institute Executive Plaza North, Room 540 Bethesda, MD 20892 Telephone: (301) 496-6085 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 10/88, reprinted 9/89) must be used in applying for these grants. These forms are available at most institutional business offices; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD 20892, telephone 301/496-7441; and from the NCI Program Director named above. The RFA label available in the 10/88-9/89 revision of the PHS 398 application form must be affixed to the bottom of the face page. 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 number and title must be typed on line 2 of the face page of the application form, "Response to Specific Program Announcement" and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and four signed, exact photocopies, in one package to the address below. The photocopies must be clear and single sided. DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 5333 Westbard Avenue Bethesda, MD 20892 At time of submission, send two additional copies of the application to: REFERRAL OFFICER Division of Extramural Activities National Cancer Institute Westwood Building, Room 838 5333 Westbard Avenue Bethesda, MD 20892 If the applicant has an approved assurance covering the research (multiple project assurance for animal subjects), the applicant must provide, with the application, verification of the institutional animal care and use committee (IACUC) approval if animals are involved. These reviews and approvals must occur PRIOR TO SUBMISSION of the applications for award and the certifications and verifications must be SUBMITTED WITH the applications. Failure to provide required certifications and verifications within applications could result in deferral or rejection. If animals will be subjects of the research at PERFORMANCE SITES OTHER THAN THE APPLICANT ORGANIZATION, the applicants must identify, within the application, the assurance status of each participant. Failure to provide this information within applications could result in deferral or rejection. Applications must be received by April 28, 1992. If an application is received after that date, it will be returned to the applicant. 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. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to the RFA is an NCI program staff function. Applications will be judged to determine responsive to the goals and objectives of the RFA. Applications judged non-responsive will be returned to the applicant but may be submitted as investigator-initiated research grants at the next receipt date. Questions concerning the relevance of proposed research to the RFA may be directed to program staff listed in the INQUIRIES section. In cases where the number of applications is large compared to the number of awards to be made, the NCI may conduct a preliminary scientific peer review to eliminate those applications that clearly are not competitive. The NCI will withdraw from further competition those applications judged to be noncompetitive and notify the applicant and institutional business official. Those applications judged to be both competitive and responsive 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. o The scientific merit, technical and medical significance of the proposed research, including the adequacy and quality of the methodological approach and the research design. Familiarity with the proposed techniques must be demonstrated, e.g., by the presentation of preliminary data. o The expertise and qualifications of the Principal Investigator and proposed staff and/or collaborators to perform the proposed experiments. o Documentation of the adequacy of the facilities and resources. o Appropriateness of the proposed budget and duration in relation to the proposed research. The second level of review by the National Cancer Advisory Board considers the special needs of the Institute and the priorities of the National Cancer Program. AWARD CRITERIA The anticipated date of award is September 1992. INQUIRIES Written and telephone inquiries concerning the objectives and scope of this RFA and inquiries about whether or not specific proposed research would be responsive are encouraged and may be directed to Dr. Kenneth Cremer at the above address. The Program Director welcomes the opportunity to clarify any issues or questions from potential applicants. Direct inquiries regarding fiscal matters to: Mr. Joseph H. FitzGerald Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800, Ext. 15 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Number 93.393, Cancer Cause and Prevention Research. Awards are made under the authorization of the Public Health Service (PHS) Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 U.S.C. 241 and 285) and administered under PHS grant policies and Federal Regulations 42 CFR Part 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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