PA-01-042: NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY

Department of Health
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NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY Release Date: January 10, 2001 PA NUMBER: PA-01-042 National Cancer Institute Letter of Intent Receipt Dates: June 4, 2001 and February 5, 2002 Application Receipt Dates: July 12, 2001 and March 13, 2002 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. This Program Announcement replaces PAR-99-019, which was published in the NIH Guide, November 27, 1998. PURPOSE This Program Announcement (PA) encourages the use of non-mammalian organisms to aid in the discovery of new cancer therapies. The use of non-mammalian organisms for the development of new strategies for prevention, early detection, and treatment of cancer is cited in the NCI’s 2002 Bypass Budget ( http://plan2002.cancer.gov). The goal of this PA is the identification of key genes and gene products which are altered in human cancer and could be exploited as intervention points or targets for the discovery of new cancer prevention or treatment drugs. Projects could focus on validating inferences already drawn from comparative study of cancerous and normal cells, exploring promising leads from an evaluation of mutations known to be associated with cancer development, or testing hypotheses generated by the identification of new and unknown gene products, such as those sequenced through the NCI’s Cancer Genome Anatomy Project (CGAP) (http://www.ncbi.nlm.nih.gov/ncicgap). For example, projects may include development of organisms in which genes in key pathways or processes are mutated or organisms in which human transgenes are expressed to simulate changes known to occur in human cancers. These genetic manipulations could present a proof of principle or validation of the importance of the target genes to the development of cancer. Some examples of genes that are well studied in model organisms and known or strongly suspected of involvement in cancer include oncogenes, proto- oncogenes, some cell cycle and signal transduction genes, and DNA repair genes. The use of multiple grant funding mechanisms allows support for a broad range of projects at various stages of development. The exploratory/developmental R21 mechanism supports pilot projects or feasibility studies for new or underdeveloped approaches. Accordingly, a sound rationale and a well designed research plan, but not preliminary data, are required. The R01 supports more advanced projects and collaborative research efforts between experts in non- mammalian biology and investigators with experience in mammalian cancer models for comparative or proof of principle, validation studies. This PA will expire on March 14, 2002, unless reissued. NIH Grants policies apply to these awards. RESEARCH OBJECTIVES The goal of cancer therapy is to eliminate malignant cells while sparing normal cells. Current clinically important drugs act as cytotoxic agents by binding to or damaging DNA, altering cellular processes, or binding to structural proteins such as tubulin causing disruption of cell function. Generally, they were discovered as anti-proliferatives without specific consideration to site of action. Thus, as might be expected, they show significant toxicity to normal cells which limits their clinical usefulness. Targeting specific cell control elements that are altered in tumor cells provides a new and potentially valuable approach to identify new, more selective, and less toxic agents for the cancer armamentarium. By focusing on a specific target or a target operating in a defined pathway, it should be possible to reverse, stop or delay cancer progression. A vast array of altered proteins, regulatory processes, and signaling pathways have been implicated in cancer genesis and progression. However, only a select few, such as ras farnesylation and various protein tyrosine kinases, have been approached for cancer drug discovery. Determining which in this multitude of alterations and mutations are sites of vulnerability and are thus of importance for intervention, as well as designing approaches to exploit these sites for cancer drug discovery, are clearly daunting tasks. Non-mammalian organisms offer an extraordinary opportunity to evaluate the importance and vulnerability of these sites and to suggest which could be of importance for drug discovery. Key regulatory pathways among eukaryotic organisms demonstrate a striking similarity. Importantly, cancer gene homologs and functional pathways containing homologs are of importance in a wide variety of cells including those of non-mammalian origin. Although not always of identical importance in humans, common pathways or at least portions of such pathways could be considered to be functional cassettes performing similar tasks within cells or organisms. For this reason, the use of non- mammalian organisms, which are easier to manipulate genetically, has been valuable in defining new pathways relevant to neoplasia as well as functional relationships among the various pathways. For example, at least 100 genes have been identified in yeast which have been classified as damage control elements whose gene products are involved in functions such as DNA repair, cell cycle regulation, and spindle formation. Several have been shown to have homologs in human cells such as the MSH2 and MLH1 repair genes and the ATM (ataxia-telangiectasia) cancer susceptibility gene. Likewise, C. elegans biology has defined several genes important to apoptotic pathways with clear homologs in humans. Drosophila have recently highlighted the importance of the sonic-hedgehog pathway, whose members include a gene inactivated in basal cell carcinoma. Xenopus and zebrafish are additional non-mammalian organisms whose biology is being actively studied and are known to contain homologs of cancer relevant proteins. Importantly, genomic sequences of non-mammalian organisms are known as in the case of yeast or are being determined at a rapid pace, thus providing a valuable asset for delineating the complexities of signaling pathways and control functions. Applications without a strong rationale for cancer relevance would not be responsive to this PA. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) research project grant (R01) mechanism and the exploratory/developmental grant (R21) mechanisms. Applicants will be responsible for the planning, direction, and execution of the proposed project. All PHS and NIH grants policies will apply to applications received and awards made in response to this PA. Applicants for the R21 grant mechanism may request up to $100,000 direct costs (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. Support may not exceed two years. Though the size of award may vary with the scope of research proposed, it is expected that R21 applications will stay within the budgetary guidelines for an exploratory/developmental project. The R21 grants are non-renewable, and competitive continuation of projects developed under this program will be through the R01 research grant mechanism. Applications for the R01 grant mechanism may not exceed five years. Collaborative arrangements involving more than one institution are encouraged, including participation of the pharmaceutical industry where appropriate. 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 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. 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: George S. Johnson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 8153 6130 Executive Boulevard Bethesda, MD 20892-7456 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: johnsong@exchange.nih.gov Direct inquiries regarding fiscal matters to: Jane Paull National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 846-1013 FAX: (301) 846-5720 Email: paullj@gab.nci.nih.gov Direct inquiries regarding review issues 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 LETTER OF INTENT Prospective applicants are asked to submit, by the dates 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 numbers 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 NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this PA. 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. Application 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, e-mail: grantsinfo@nih.gov. The title and number of this PA must be typed in line 2 on the face page of the application form and the YES box must be marked. For applicants with internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call Dr. George S. Johnson, as listed in INQUIRIES, with any questions regarding adherence to the guidelines of their proposed project to the goals of this PA. SPECIFIC INSTRUCTION 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 $250,000 per year for R01 and, up to a total direct cost request of $100,000 per year ($125,000 if there are consortium/contractual Cost) for R21. (Applications that request more than $250,000 direct costs for an R01 in any year must follow the traditional PHS 398 application instructions.) 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. 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. o 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 Provide an additional narrative budget justification if there is a change in the number of modules requested from year to year. 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 PA 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 ensure that the application is received in sufficient time for the review, send two additional copies 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 Email: tf12w@nih.gov Applications must be received by the receipt dates listed at the top of the first page of this PA. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an introduction addressing the previous critique. 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 a special emphasis panel convened by the Division of Extramural Activities of the National Cancer Institute 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. Within this framework the purpose of this PA is the identification of new approaches for cancer discovery through exploitation of unique features of non-mammalian organisms. Meritorious projects would include those which identify a novel regulatory process in the non-mammalian organism which has high relevance to human cancer. 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 an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 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, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as subjects in Clinical Research. AWARD CRITERIA Applications will compete for available funds with all other approved 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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 is 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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS Effective October 1, 2000, the NIH requires education on the protection of human research participants for all investigators submitting NIH application for grants or proposals for contracts or receiving new or non-competing awards for research involving human subjects. All investigators proposing research involving human subjects should read the above-referenced policy that was published in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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, Non-mammalian Organisms as Models for Anticancer Drug Discovery , is related to the priority area of cancer. 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. 93.395, Cancer Treatment 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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