BIOTECHNOLOGY TRANSFER TO EPIDEMIOLOGIC STUDIES IN CANCER NIH GUIDE, Volume 21, Number 27, July 31, 1992 RFA AVAILABLE: CA/ES-92-23 P.T. 34 Keywords: Cancer/Carcinogenesis Biological Markers Epidemiology Risk Factors/Analysis National Cancer Institute National Institute of Environmental Health Sciences Letter of Intent Receipt Date: October 22, 1992 Application Receipt Date: November 19, 1992 THE REQUEST FOR APPLICATION (RFA) ANNOUNCED IN THIS NOTICE CONTAINS ESSENTIAL INFORMATION FOR THE PREPARATION OF AN APPLICATION. POTENTIAL APPLICANTS MAY OBTAIN THE RFA FROM THE CONTACT NAMED IN INQUIRIES BELOW. PURPOSE The Extramural Programs Branch, Division of Cancer Etiology, National Cancer Institute (NCI), and the Scientific Programs Branch, Division of Extramural Research and Training, National Institute of Environmental Health Sciences (NIEHS), invite investigator-initiated research grant applications to further the effective use of biomarkers of exposure or susceptibility in future epidemiologic studies of cancer etiology. 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, Biotechnology Transfer to Epidemiologic Studies in Cancer, 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 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 Applications may be submitted by domestic and foreign non-profit and for-profit institutions, public and private, such as colleges, universities, hospitals, research 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 program will be supported by traditional research project (R01) grants and Interactive Research Project grants (IRPG). Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000, revised October 1, 1990. The earliest anticipated date of award is July 1, 1993. This RFA is a one-time solicitation. The total project period for applications submitted in response to the present RFA may not exceed three years. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Competitive continuation applications will compete with all other unsolicited applications and be reviewed by standing Division of Research Grants study sections. If the NCI and NIEHS determine that there is a sufficient continuing program need, a request for renewal applications may be announced. FUNDS AVAILABLE The estimated funds (total costs) available for the first year of support for this initiative is $1.5 million. The expected number of awards is five to seven. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI and the NIEHS, the award of grants pursuant to this RFA is also contingent upon the availability of funds for this purpose. SPECIAL REQUIREMENTS Successful grant awardees under this RFA are strongly encouraged to participate in an annual program meeting of one or two days' duration in Bethesda, Maryland, during the first and third years and in Research Triangle Park, North Carolina during the second year. Program directors from the NCI and the NIEHS will coordinate the meeting that will review and assess overall progress and provide the opportunity for investigators to exchange information and discuss methodological issues. The respondents must request sufficient funds within the budget to accommodate expenses for one to two participants at these meetings. The application should include a statement indicating a willingness to comply with this requirement. RESEARCH OBJECTIVES Background A large proportion of human cancers are thought to be attributable to environmental factors, some of which may interact with host susceptibility states. The problem of identifying the effects of specific risk factors and evaluating their relative importance is a challenging one. Multiple exposures to a variety of agents over extended periods are the rule rather than the exception, and many populations are exposed to low levels of carcinogens. A wide range of susceptibility mechanisms may be involved in processes of carcinogenesis, and the long latency period of many cancers may make cause-effect relationships elusive. Traditional methods in epidemiology have estimated exposure to carcinogens on the basis of surrogate measures. These have included, for instance, questionnaire data on lifestyle factors such as diet and smoking, record of job titles or past employment in a particular industry, or interview information on use of medications. Discovery of the association between smoking and lung cancer is a classical example, demonstrating the merit of these techniques. In etiological studies, the addition of measured parameters in the form of biological markers (biomarkers) can strengthen epidemiologic findings, especially where there may be a weak causal effect, differences in exposure level, complex mixtures of agents, or interactions of risk factors. Appropriate biomarkers can reduce misclassification of exposures, increase accuracy, and enhance study power to resolve exposure-cancer relationships. Exciting opportunities have emerged from the recent revolution in molecular biology and genetics. Laboratory advances offer unprecedented capabilities to measure carcinogenic factors at the cellular or molecular level and to detect their interaction with cellular constituents. A variety of biomarkers (e.g., biochemical, molecular, genetic, immunologic) show significant promise of improving exposure assessments (e.g., hemoglobin or DNA adducts), identifying inherited and acquired host susceptibility (e.g., p53 gene mutations), and detecting cellular and subcellular events representing predisposing disease states, intermediate outcomes, and early stages of cancer (e.g., sister chromatid exchanges). To date, most of the evidence about biomarkers has been derived from experimental systems, with only limited testing in human subjects in well-controlled field studies. Pilot studies in small populations of humans have demonstrated the utility of certain biomarkers: cellular assays indicating pathobiological responses to carcinogens (e.g., cytogenetic changes) and techniques that assess inherited or acquired host susceptibility factors (e.g., metabolic polymorphic phenotyping). However, a wide range of interindividual variability and methodological issues remain to be resolved before these procedures can be applied to large-scale epidemiologic investigations. Other The goal of this initiative is to stimulate investigations designed to validate and apply biomarkers of exposure or susceptibility in epidemiologic research in cancer etiology. For biomarkers demonstrated to have utility, assessment of the extent of intra- and inter-individual variability is important. Validation procedures should consider determinations of range of normal values, as well as sensitivity, specificity, and predictive value. The influence of biological variables such as age, sex, race, ethnicity, nutritional status, preexisting disease, and lifestyle should be appropriately addressed. Inter-institutional collaborations between laboratory scientists from several disciplines and epidemiologists are encouraged to promote integrated planning of study protocols and experimental methods as well as the conduct of research. Extension of an ongoing epidemiologic study by the addition of a laboratory component can be proposed. Laboratory investigations will be acceptable if human subjects or specimens are being tested. Whenever possible, research design should utilize shared laboratory and specimen resources. Ease of study conduct and expense, as well as collection, storage, and transport problems should be considered. Projects will be evaluated on their potential for enhancing the understanding of cancer etiology and strategies for prevention. We particularly encourage studies with relevance to breast, ovarian, prostate, and cervical cancers. The initiative permits a range of investigations in molecular epidemiology relevant to cancer etiology, including, but not limited to: o Demonstration of the feasibility of developed biomarkers for epidemiologic research (e.g., heterocyclic amine food mutagens, benzene-DNA adducts, thymine glycol, mutation of the hypoxanthine guanine phosphoribosyl transferase (HGPRT) gene); o Validation of biomarkers in exposed and unexposed population subgroups (e.g., ethnic and minority populations, family units, occupational cohorts, patients taking chemotherapeutic agents or other medicinal compounds); o Determination of levels of agreement of mutually confirmatory methods of analyses for measuring the same biomarker (e.g., DNA adducts by physico-chemical, immunoassay, and postlabelling methods) with consideration of inter-and intra-laboratory variability; o Comparison of biomarkers or combinations of biomarkers in different sources of specimens such as human cells, tissues, organs, and body fluids; o Determination of specific sampling conditions (e.g., timing, seasonality, repetitive or serial testing) in a chronobiologic fashion including host/environmental factors with/without interactions (e.g., dietary, viral, hormonal) that may influence validity, reliability, and reproducibility; o Establishment of background or reference levels in normal or unexposed populations (e.g., cytochrome P450 isoenzymes, glucuronyltransferase, covalent RNA or protein adducts, arylamine-macromolecular adducts). STUDY POPULATIONS SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDIES For projects involving clinical research, NIH requires applicants to give special attention to the inclusion of women and minorities in study populations. If women or minorities are not included in the study populations for clinical studies, a specific justification for this exclusion must be provided. Applications without such documentation will not be accepted for review. LETTER OF INTENT Prospective applicants are requested to submit, by October 22, 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, the information that it contains is helpful in planning for the review of applications. It allows NCI and NIEHS staff to estimate the potential review workload. The letter of intent is to be sent to Dr. Kumiko Iwamoto at the address under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on form PHS 398 (rev. 9/91), available at most institutional business offices and 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. The format and instructions applicable to research grant applications must be followed. Applications must be received by November 19, 1992. REVIEW CONSIDERATIONS Each application submitted in response to the RFA will be given dual institute assignment to the NCI and the NIEHS. The primary assignment will be determined later by mutual agreement of the Program Directors from the supporting programs. Applications judged to be competitive will be reviewed by an appropriate review panel of the Division of Extramural Activities, NCI. Second level review will be by the National Cancer Advisory Board or the National Advisory Environmental Health Sciences Council. All applications will be reviewed in competition with each other. The factors that will be considered in evaluating grant applications that are responsive to this RFA will include: scientific, technical, or medical significance and originality of proposed research; appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; qualifications and research experience of the Principal Investigator and staff, particularly but not exclusively in the area of the proposed research; availability of resources necessary to perform the research; and appropriateness of the proposed budget and duration in relation to the proposed research. INQUIRIES Written and telephone inquiries concerning the RFA and the opportunity to clarify any issues or questions from potential applicants are welcome. Direct inquiries regarding programmatic issues and requests for the RFA to: Dr. Kumiko Iwamoto Extramural Programs Branch Epidemiology and Biostatistics Program Division of Cancer Etiology National Cancer Institute Executive Plaza North, Suite 535 Rockville, MD 20892 Telephone: (301) 496-9600 or Dr. William A. Suk Scientific Programs Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences Research Triangle Park, NC 27709 Telephone: (919) 541-0797 Direct inquiries regarding fiscal matters to: Ms. Jean M. Cahill Supervisory Grants Management Specialist National Cancer Institute 6120 Executive Boulevard Executive Plaza South, Suite 216 Rockville, MD 20892 Telephone: (301) 496-7800, ext. 47 or Mr. David L. Mineo Grants Management Officer Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.393, Cancer Cause and Prevention Research. Awards are made under authorization of the Public Health Service Act, Section 301(c) and Section 402 (Public Law 78-410, as amended; 42 USC 241; 42 USC 282) 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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