MOLECULAR TARGETS FOR CANCER DRUG DISCOVERY: EXPLORATORY GRANTS RELEASE DATE: November 7, 2002 PA NUMBER: PA-03-020 EXPIRATION DATE: February 2, 2003, unless reissued. National Cancer Institute (NCI) (http://www.nci.nih.gov/) APPLICATION RECEIPT DATE: February 1, 2003 This Program Announcement (PA) replaces PAR-01-045, which was published in the NIH Guide on February 2, 2001. THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The purpose of this Program Announcement (PA) is to promote a full utilization of the base of knowledge of cancer biology for cancer-relevant target validation and drug discovery for treatment and prevention. This initiative is intended to attract young investigators to embark on career choices that include drug discovery, and also experienced investigators to apply their expertise to new ventures into cancer therapeutics. That great advances have been made in the past decade in our understanding of the cell in health and disease is unquestioned. Many genes that have mutated and molecular processes that have gone awry in a cancer cell have been identified. New information on the difference between a normal and a cancer cell continues to be added to this wealth of knowledge. It is now incumbent that this knowledge be used to mount a renewed attack on cancer - for its prevention and its treatment. The challenge is to identify, characterize and validate new molecules and molecular processes that can serve as targets for drug discovery and initiate a new age of therapeutics. While the empiric approach may have yielded its dividends, the new paradigm demands a more reasoned and knowledge-based approach. For a better appreciation of the contextual frame work of this initiative, see the NCI document - The Nation's Investment in Cancer Research: Plans and Priorities for Cancer Research - at http://plan.cancer.gov As a companion to this announcement, an additional initiative on Molecular Targets for Cancer Drug Discovery under the Small Business Innovation Research (SBIR) and Small Business Technology Transfer(STTR) mechanisms is also being issued (See http://grants.nih.gov/grants/guide/pa-files/PA-03- 021.html). More information can be found on homepages of the Developmental Therapeutics Program (http://dtp.nci.nih.gov) and of the Division of Cancer Prevention (http://dcp.nci.nih.gov). RESEARCH OBJECTIVES Background The past decade has witnessed an unprecedented accumulation of knowledge of the genetic make up and biological function of the cell. In parallel there have been technological advancements allowing ever more detailed inquiry into its structure and function. The deciphering of the human genome sequence with its boost to functional genomics and proteomics is a harbinger of things to come. A great deal is now known about the molecules and molecular processes that sustain the life of the cell. The structural and functional differences between a normal and a cancer cell are being defined with increasing precision. A detailed understanding of such cellular processes as signal transduction from within or without, cell cycle regulation, apoptosis, migration and metastasis are revealing new points of vulnerability in a cancer cell. The events that occur in the initiation and in the maintenance of cancer, including metastasis, are being delineated with increasing confidence. Thus, the stage is set for exciting new approaches in drug discovery for cancer prevention and treatment. Objectives The objective of this initiative is to support exploratory studies into previously unexplored or under-explored areas of research with the goal of drug discovery. The focus will be on new molecular targets and new agents that modulate them. The exploration of new targets will include their identification and characterization, and establishment of their relevance to cancer. Novel ways of looking at and exploiting previously known targets also would be appropriate, but mere extension or reconfirmation of what is already known will not be. These targets may be relevant to any type of cancer, including pediatric cancers. The targets may encompass any cellular process, from cell cycle and apoptosis to angiogenesis and metastasis, and also the immune system. However, the process must be clearly altered in cancer cells and well defined in molecular terms for monitoring and manipulation. The development of new assays and innovative technologies for monitoring will not be sufficient as stand alone projects but their development in conjunction with molecular target identification and validation will be appropriate. The search for molecules or agents that will redirect the behavior of the target and subvert its deleterious effect would be a component of this PA. These agents could be chemical or biological, man made or naturally occurring, but well characterized or subject to characterization as potential therapeutic agents. The particular approach or experimental system to be used is left to the imagination and creativity of the investigator, consistent with the demands of the specific objective or hypothesis. Unless otherwise justified, the approach should be quantitative and specific, whether in vitro or in vivo, and not based on global effects. Measurement of overall cell growth or tumor volume can be acceptable only if they demonstrably can be linked to modulation of a specific target(s). Use of modern tools of drug discovery such as rational drug design or high throughput screening of combinatorial libraries would be appropriate. Preliminary data are not a requirement, but the proposal should reflect clear reasoning and demonstrable feasibility. While the hypothesis-driven nature of the proposal may not be overtly evident, it should be reason-driven. The NCI compound libraries and the Natural Products Repository are available to qualified investigators for research purposes. The information for these resources can be found at http://dtp.nci.nih.gov. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) exploratory/developmental (R21) grant award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. You may request up to $100,000 direct costs (four budget modules) per year unless your 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. This PA uses just-in-time concepts. It also uses the modular budgeting format. (See http://grants.nih.gov/grants/funding/modular/modular.htm). ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific issues in cancer treatment to: Suresh K. Arya, Ph.D. Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, EPN 8153 Bethesda, MD 20892-7456 (For express/courier service: Rockville, MD 20852) Tel: 301-496-8783 Fax: 301-402-5200 Email: aryas@exchange.nih.gov Direct your questions about scientific issues in cancer prevention to: Winfred F. Malone, Ph.D. Chemoprevention Agents Development Research Group Division of Cancer Prevention National Cancer Institute 6130 Executive Boulevard, EPN 200A Bethesda, MD 20892-7322 (For express/courier service: Rockville, MD 20852) Tel: 301-594-0460 Fax: 301-402-0553 Email: malonew@mail.nih.gov o Direct your questions about financial or grants management matters to: Eileen M. Natoli Grants Administration Branch National Cancer Institute 6120 Executive Blvd. – EPS 243 Bethesda, MD 20892 Telephone: (301) 496-8791 Email: natolie@gab.nci.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001), except that sections a-d of the Research Plan may not exceed 15 pages, including tables and figures. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted on February 1, 2003. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed 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) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE CENTER FOR SCIENTIFIC REVIEW WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-012.html) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. 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. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. Applications that are complete and adhere to the guidelines of this PA will be evaluated for scientific and technical merit by an appropriate peer review group convened by CSR in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique. o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score. o Those that receive a priority score will undergo a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/ HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02- 005.html. Guidance for investigators and institutional review boards regarding research involving human embryonic stem cells, germ cells, and stem cell-derived test articles can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02- 044.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers 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 is related to one or more of the priority areas. 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, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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