Full Text CA-96-008 STUDIES OF THE VIRAL ETIOLOGY OF AIDS-ASSOCIATED MALIGNANCIES NIH GUIDE, Volume 25, Number 4, February 16, 1996 RFA: CA-96-008 P.T. 34: K.W. 0715008, 0715035, 1002045, 0755030 Keywords: National Cancer Institute Letter of Intent Receipt Date: April 15, 1996 Application Receipt Date: May 24, 1996 PURPOSE The National Cancer Institute (NCI) invites investigator- initiated research grant applications for support of basic studies on the role of viruses and other biological agents in the etiology and biology of malignancies associated with AIDS, including, but not limited to, Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphomas. 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, Studies of the Viral Etiology of AIDS-Associated Malignancies, is related to the priority areas of cancer and women's health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.017-001-00474-0 or Summary Report: Stock No.017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). 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 and local governments, and eligible agencies of the Federal government. Foreign institutions and organizations are not eligible for the First Independent Research Support and Transition (FIRST) Awards (R29). Applications from minority and women investigators are encouraged. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) research project grant (R01) and the FIRST Award (R29). The total direct cost award for the five-year R29 grant period may not exceed $350,000 and the direct cost award in any R29 budget period may not exceed $100,000. Applicants will be responsible for the planning, direction, and execution of the proposed project. The total project period for each application submitted in response to this RFA may not exceed five years. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will also vary. FUNDS AVAILABLE Approximately $1,000,000 in total costs per year for up to five years will be committed to fund applications that are submitted in response to this RFA. It is anticipated that five to six awards will be made. The level of funding is dependent upon the receipt of a sufficient number of applications of high scientific merit. The earliest feasible start date for the initial awards will be September 30, 1996. Although this program is provided for in the financial plans of the NCI, the award of grants pursuant to this RFA is contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Patients infected with the human immunodeficiency virus (HIV) are at high risk for the development of opportunistic infections and neoplastic sequelae, particularly Kaposi's sarcoma (KS) and lymphoproliferative diseases such as non-Hodgkin's lymphomas (NHL). Two NCI-sponsored workshops were held to address problems and research involving AIDS-associated neoplasms. A workshop entitled "The Biology of AIDS Lymphomas" was held on May 11-12, 1992 in which participants assessed the status of research on AIDS-NHL. An "AIDS- Related Malignancies" workshop was held on January 11, 1993 to stimulate ideas for novel and innovative treatment of AIDS malignancies. This RFA is issued in accordance with the workshop participants' recommendation that extramural research be stimulated in this area with set-aside funds. KS was once a rare tumor, but a sudden increase was observed in the early 1980s in homosexuals newly diagnosed with AIDS. KS is now diagnosed at initial presentation in nearly 10 percent of AIDS patients. AIDS-KS is characterized by dermal lesions but may progress and result in visceral involvement in the gastrointestinal tract, lungs and liver. Although the incidence of KS remains fairly constant during the first seven or eight years following HIV infection, it increases in the later stages of AIDS with advancing immune dysfunction and disease progression. Natural history studies indicate that KS develops almost exclusively in homosexual men, suggesting that a sexually transmissible agent(s) may be involved in the etiology of KS. KS is characterized by a proliferation of spindle-like cells, and the lesions are infiltrated by inflammatory cells, fibroblasts and endothelial cells. Cells from KS lesions produce cytokines and growth factors that promote autologous cell growth and the recruitment and growth of normal cells. The HIV tat regulatory protein functions as a growth factor for cultured AIDS-KS cells and tat-transgenic mice develop skin lesions similar to human KS lesions, suggesting tat as a pathogenic link of HIV to KS. However, the mechanism(s) underlying the pathogenesis of this complex tumor is not understood. The etiology of KS has not been established and the factors and mechanisms involved in the growth of KS cells and tissues have not been fully investigated. Lymphomas are a heterogeneous group of neoplasms observed as lymph node tumors in all population groups of AIDS patients. Tumor development is associated with B-cell activation and oligoclonal proliferation leading to monoclonal or possibly polyclonal expansion of B-cells. The majority of AIDS lymphomas are high grade NHLs, exhibiting aggressive and metastatic growth properties and are refractory to standard therapies. An unusually high rate of extranodal lymphoma occurrence is seen in the central nervous system (CNS), gastrointestinal tract, bone marrow, heart, skin, lung, oral cavity and testis. Approximately 10 to 20 percent of AIDS-NHL are primary CNS tumors, rare in the normal population. These properties suggest that several mechanisms may be responsible for the development of lymphomas in HIV-infected populations. Since the etiology of lymphoid malignancies in the setting of HIV infection is not known, there are opportunities for expanded research. The direct role of viruses in the etiology of AIDS-associated malignancies has been suggested. HIV undergoes a rapid rate of mutation in patients, with a number of viral variants existing in an individual's population of HIV at any time. Some variants may be more lymphotropic or have growth advantages when compared to other variants. In addition, viral superantigens have been hypothesized to play a role in B-cell expansion and lymphomagenesis. The mechanism by which a viral protein(s) might function as a superantigen(s) and the relationship to lymphomagenesis are not known, and thus constitute important areas for additional virologic emphasis. Virus-host interactions may play a role in oncogenesis. There has been an increased incidence of NHLs in relation to reactivation of Epstein-Barr virus (EBV) or direct antigenic stimulation of lymphoid cells by EBV. Chromosome translocations and c-myc gene rearrangements are observed in 75 percent of lymphomas in some groups of HIV-infected individuals while EBV is detected in only 25 to 40 percent of the lymphomas in other HIV-infected populations, suggesting that co-factors other than EBV or molecular mechanisms other than chromosome translocation may be involved in the etiology of these lymphomas. AIDS lymphomas may arise through distinct pathogenic processes including: (1) monoclonal B-cell lymphomas associated with c-myc gene rearrangement and the presence of EBV genomes; (2) polyclonal B-cell lymphomas without evidence of EBV involvement; and (3) monoclonal primary CNS lymphomas associated with EBV infection but lacking detectable c-myc rearrangement. Additionally, recently detected rare T-cell NHLs were described in which the indirect role of HIV was hypothesized. Cellular proteins such as c-ras oncogene and p53 may play a role in a multi-stage progression of lymphoid neoplasia. The diversity in the possible etiology of AIDS lymphoid malignancies, in pathology and cell types, and the molecular characteristics of these neoplasms lead to the suggestion that lymphomagenesis in the setting of AIDS may be several distinct disease processes that will require an expanded multidisciplinary research approach. Research Goals and Scope The goal of this RFA is to stimulate research on the role of viruses and other biological agents in the etiology and biology of malignancies associated with AIDS, including but not limited to Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphomas. Possible oncogenic or etiologic agents that might interact with HIV include the Epstein-Barr virus, cytomegalovirus and other human herpesviruses, human papillomaviruses, human T-lymphotropic viruses or unknown but suspected retroviruses or other microbes. Research might also focus on etiologic agents functioning as a co-factor(s) in the context of HIV infection or on HIV serving as a co-factor in the context of other viral or microbial infections. Proposed areas of investigation might include but are not limited to: (1) the role of viruses and/or biological factors and/or co-factors in the etiology of AIDS-associated malignancies; (2) interactions between viral nucleic acid sequences, viral and cellular genes and/or proteins which might be involved in the initiation and progression of AIDS- associated malignancies, e.g., interactions with cellular oncogenes; (3) the role of direct and indirect processes, such as autocrine and paracrine mechanisms and effects, by which single or multiple viral or microbial infections play a role in the initiation and progression of AIDS-associated neoplasms; (4) the use of currently available, appropriate and well-justified animal models to investigate the molecular basis of AIDS-associated malignancies; and (5) investigations of the alteration of pathogenesis and oncogenesis as a consequence of the immune status of the patient. SPECIAL REQUIREMENTS The Principal Investigator of R01 applications must spend a minimum of 20 percent effort on this project. FIRST Award Principal Investigators must devote a minimum of 50 percent effort on this project. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was reprinted in the Federal Register of March 28, 1994 (59 FR 14508-14513) and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by April 15, 1996, a letter of intent that includes a descriptive title and brief summary of the proposed research, the name, address, and telephone number of the Principal Investigator(s), the names of other key personnel and collaborators, the participating institutions, and the number and title of the RFA in response to which the application may be submitted. A letter of intent is not required, is not binding, and does not enter into the review of a subsequent application. However, it is requested in order to provide an indication of the number and scope of applications to be reviewed, thus allowing 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 at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: girg@drgpo.drg.nih.gov; and from the NCI Program Director listed under INQUIRIES. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 (rev. 5/95) 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 number and title must be typed on line 2 of the face page of the application form, "Response to Specific Request for Application or Program Announcement," and the YES box must be marked. 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. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact, clear and single-sided photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 USA (for express/courier service) At time of submission, send two additional copies of the application to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 MSC 7405 Bethesda, MD 20892-7405 Bethesda, MD 20816 (for express/courier service) It is important to send these copies at the same time that the original and three copies are sent to the DRG; otherwise the NCI cannot guarantee that the applications will be reviewed in competition with other applications received by the designated receipt date. Applications must be received by May 24, 1996. An application received after that date will be returned to the applicant. The Division of Research Grants (DRG) 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 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. No addenda or appendix materials will be accepted after the receipt date unless explicitly requested by the Scientific Review Administrator. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by DRG 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 responsiveness 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 the Program Director under INQUIRIES. 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 NCI, in accordance with NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Cancer Advisory Board. The review criteria for the RFA will be: 1. Extent to which the proposed research addresses the goals of the RFA. 2. The scientific merit, technical and medical significance of the proposed research, including the appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research. Familiarity with the proposed techniques should be demonstrated by the presentation of preliminary data. 3. The demonstrated research experience, expertise and qualifications of the principal investigator and proposed staff and/or collaborators to perform the proposed experiments. 4. Documentation of the adequacy of the facilities and resources necessary to perform the research. 5. Where applicable, the appropriateness of an animal or tissue culture model system chosen for the experiments proposed and the potential relevance of the model system to AIDS-associated malignancies. 6. Where applicable, the demonstration of the availability and access to appropriate human tissue necessary to perform the proposed research, the availability of clinical information associated with human samples, and adequacy of the plans for the inclusion of females and minorities. 7. The adequacy of provisions for the protection of human subjects and the humane treatment of research animals. 8. Appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The earliest anticipated date of award is September 30, 1996. Factors, including the scientific and technical merit reflected in the priority score, availability of funds and relevance to selected areas of programmatic emphasis will be used to make award decisions. 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. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issue to: Kenneth J. Cremer, Ph.D. Division of Cancer Biology National Cancer Institute Executive Plaza North, Suite 540, MSC 7398 Bethesda, MD 20892-7398 Telephone: (301) 496-6085 FAX: (301) 496-2025 Email: CREMERK@EPNDCE.NCI.NIH.GOV Inquiries regarding fiscal matters may be directed to: Mr. Joseph H. FitzGerald Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800, Ext. 215 Email: FITZGERJ@GAB.NCI.NIH.GOV 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 or 45 CFR Part 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 and contract 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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