DEVELOPMENT OF HIGH-YIELD TECHNOLOGIES FOR ISOLATING EXFOLIATED CELLS IN BODY FLUIDS Release Date: November 15, 2000 PA NUMBER: PAR-01-019 (see replacement PA-02-086) National Cancer Institute Letter of Intent Date: March 6, 2001, October 11, 2001 Application Receipt Date: April 10, 2001, November 15, 2001 THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The purpose of this Program Announcement (PA) is to develop novel technologies for capturing, enriching, and preserving exfoliated abnormal cells in body fluids or effusions and to develop methods for concentrating the enriched cells for biomarker studies. In body fluids, such as sputum, the number of exfoliated tumor cells is often small compared to the number of non-neoplastic cells. Therefore, the detection of exfoliated abnormal cells by routine cytopathology is often limited because few atypical cells may be present in the specimen. Furthermore, there may be difficulty in separating dysplastic cells from non-specific reactive changes and degenerating cells or variation in diagnostic criteria. Furthermore, exfoliated cells are frequently contaminated with normal cells, bacteria, and other cellular debris, which makes molecular analysis difficult without physical separation of the neoplastic cells. Thus, the development of enrichment methods is a prerequisite for the routine detection of small numbers of exfoliated cells and small amounts of subcellular materials in biological fluids for molecular analysis. Small businesses are encouraged to respond to a parallel RFA CA-01-016 (see http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-01-016.html) of identical scientific scope that uses the SBIR and STTR mechanisms. RESEARCH OBJECTIVES Background The most common human tumors arise from epithelial surfaces (e.g. colon, lung, prostate, oral cavity, esophagus, stomach, uterine cervix, bladder). Their development often becomes apparent when tumor cells exfoliate spontaneously into sputum, urine, or even into various effusions. The molecular and genetic abnormalities within these exfoliated cells could be used to detect and identify precancerous lesions or very early stage cancer if highly sensitive technologies were clinically available to identify the few abnormal cells among millions of normal cells. For example, detection of widespread microsatellite instability (MSI), as demonstrated by expansion or deletion of repeat elements of DNA, may be adapted for exfoliated cells in general. With the advent of PCR-based detection of DNA from rare neoplastic cells in body fluids, mutations have been detected in ras genes from the stool of patients with colorectal cancer, and in p53 from the urine of patients with bladder cancer and in the sputum of patients with lung cancer. As these assays are complex and technically challenging, they depend on the development of novel technologies for isolating and enriching exfoliated cells. Abnormal exfoliated cells can be routinely identified by cytologic examination of brushings and fluids, for instance, from bronchi, pancreatic ducts, voided urine and tapping of effusions. Currently fluids are usually processed by centrifugation or membrane filtration. However, the detection of abnormal exfoliated cells, for instance, cancer cells by routine cytopathological examination may be limited because the number of abnormal cells may be very small compared to the number of normal cells. Alternatively, the cellular and nuclear changes in abnormal cells may be minimal compared to normal cells. This is particularly true of urine cytology, where many low-grade papillary lesions are often missed on cytological examination. New PCR-based technologies may substantially enhance the sensitivity, but current technologies for isolating exfoliated cells are too cumbersome to be of practical utility. Finding molecular and genetic biomarkers of early cancer represents an extraordinary opportunity for the National Cancer Institute (NCI) and is particularly important in detecting the emergence of precancerous cell populations. In these earliest stages of neoplastic development, lesions should be amenable to complete eradication. This has been well demonstrated in cervical neoplasia, where screening for brushed exfoliated cells has resulted in a 70% or greater reduction in cervical cancer mortality. Brushing of the esophagus or stomach is commonly performed during endoscopic examination. Goals and Scope In pursuit of these goals, the NCI invites applications to address the following areas: o development of novel technologies for identifying abnormal exfoliated cells in body fluids, o development of novel technologies for capturing, enriching, and preserving abnormal exfoliated cells in body fluids, o development of enrichment methods for the isolation of tumor cells, o development of sensitive, high-throughput molecular, cytomorphometric, immunologic, and other relevant technologies to isolate tumor cells in malignant effusions for detection of low tumor burden and to help distinguish reactive cells from tumor cells. Applicants are encouraged to address the technology of enriching and isolating exfoliated cells, but they should also address their viability and usefulness for cytologic and molecular studies. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) exploratory/developmental (R21) grant mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed TWO years. Though the size of award may vary with the scope of research proposed, it is expected that applications will stay within the budgetary guidelines for an exploratory/developmental project, direct costs are limited to $100,000 (four budget modules) per year unless the application includes consortium costs, in which case the limit is $125,000 direct costs (five budget modules) per year. These grants are non- renewable and continuation of projects developed under this PA will be through the traditional unsolicited investigator initiated grant program. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, for-profit and not- for-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Sudhir Srivastava, Ph.D., M.P.H. Division of Cancer Prevention National Cancer Institute EPN, Room 330 Rockville, MD 20852 Telephone: (301) 435-1594 FAX: (301) 402-0816 Email: ss1a@nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496 -3428 FAX: (301) 402-0275 Email: tf12w@nih.gov Direct inquiries regarding fiscal matters to: Ms. Sara Stone Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 Rockville, MD 20852 (express courier) Telephone: (301) 496-9927 Fax: (301) 496-8601 Email: stones@gab.nci.nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by the dated listed on the first page of this PA, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PA 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 a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Sudhir Srivastava by the letter of intent receipt date listed. Schedule Letter of Intent Receipt: March 6, 2001, October 11, 2001 Application Receipt Date: April 10, 2001, November 15, 2001 Peer Review Date: June 2001, Feb 2002 Review by NCAB Advisory Board: September 2001, May 2002 Earliest Anticipated Start Date: December 2001, July 2002 APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. For those applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call the program contacts listed in INQUIRIES below with any questions regarding the adherence to the guidelines of their proposed project to the goals of this PA. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $100,000 per year ($125,000 if there are consortium/contractual costs).The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a form page. Provide an additional narrative budget justification for any variation in the number of modules requested. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is domestic or foreign. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this PAR and will be returned without further review. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided 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) To expedite the review process, at the time of submission, send two additional copies of the application to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt dates listed at the beginning of this PA. REVIEW CONSIDERATIONS Applications will be reviewed for completeness by the Center for Scientific Review and for adherence to the guidelines to this PA by the National Cancer Institute. Incomplete applications will be returned to the applicant without further consideration. Applications that are complete and adhere to the guidelines of this PA will be evaluated for scientific and technical merit by an appropriate scientific review group convened by the Division of Extramural Activities of the NCI in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique, and may 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. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator 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 this study address the objectives of the PA? If the aims of the application are achieved, how will this project enable the technological application of exfoliated cells? What will be the effect of these studies on the concepts or methods that drive the non-invasive approaches to cancer detection? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the 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? The initial review group will also examine: the appropriateness of proposed project budget and duration, the adequacy of plans to include both genders and minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00- 048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS. It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are clear and compelling scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 PA, Development of High-Yield Technologies for Isolating exfoliated Cells in Body Fluids., is related to priority area of Cancer Research. 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 Cancer Cause and Prevention Research. 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. 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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