and Human Services (HHS)
EXPIRED
MOLECULAR TARGET DRUG DISCOVERY FOR CANCER: EXPLORATORY GRANTS Release Date: February 2, 2001 PA NUMBER: PAR-01-045 National Cancer Institute Letter of Intent Receipt Date: May 17, 2001 Application Receipt Date: June 14, 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. This Program Announcement (PA) replaces PAR-00-060, which was published in the NIH Guide on February 18, 2000. PURPOSE The National Cancer Institute (NCI) defines new, extraordinary research opportunities through stated goals in a "Bypass Budget". Among the priorities of the 2001 and 2002 Bypass Budgets is a plan to identify and use molecular targets for the discovery and clinical testing of new anticancer agents based on the molecular mechanisms that underlie neoplastic transformations, cancer growth and metastasis. Accordingly, the Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), and the Chemoprevention Agent Development Research Group, the Division of Cancer Prevention, NCI invite exploratory/developmental grant applications (R21) to exploit molecular targets for drug discovery. New insights into our understanding of cancer cell biology provide a new opportunity for a fundamental re-ordering of approaches to cancer drug discovery. Current research in carcinogenesis has identified many enzymes, genetic lesions, and their cellular constituents associated with inhibition and progression of pre-cancers to invasive disease. Rather than depending on in vitro and in vivo screens for antiproliferative activity, investigators can now focus on new molecular targets and pathways essential for the development and maintenance of the cancer phenotype. As a result, the NCI is reorganizing its drug development programs from early drug discovery phases to the conduct of clinical trials in order to bring forward new types of agents based on strong rationales. The plan also involves changes in the clinical evaluation of new agents that will include appropriate measurements to verify target modulation. In addition to the present announcement, the NCI announces a related initiative in molecular target drug discovery for cancer treatment and prevention utilizing an additional funding mechanism: Competing Supplements for existing NCI awardees (http://grants.nih.gov/grants/guide/pa-files/PAR-01-046.html) which can extend the goals of active grants to include studies related to drug discovery. See the Home Pages of either the Developmental Therapeutics Program (http://dtp.nci.nih.gov) or the Chemoprevention Agent Development Group (http://dcp.nci.nih.gov/cb) for further information or contact individuals listed under INQUIRIES of this PA. Further information on research opportunities regarding molecular targets in drug discovery can be found in the NCI Bypass Budget, The Nation’s Investment in Cancer Research: A Budget Proposal for Fiscal Year 2001 at http://2001.cancer.gov and for 2002 at http://plan2002.cancer.gov The purpose of this Program Announcement (PA) is to reorganize the front end or gateway to drug discovery. Investigators are being asked to identify a novel molecular target, or to validate the target as a basis for cancer drug discovery, or to develop an assay for the target. Given the fact that some investigators may already have considerable preliminary data on a signaling pathway, they nevertheless may not have focused on the point of greatest vulnerability in the pathway and therefore, perhaps the optimal point of drug attack. This PA would support an investigator to validate a target and/or develop an assay based on the target. Applicants may address targets related to the treatment of established cancers, or the prevention of molecular changes which may cause cancer. Investigators may use their own creativity in defining their approach. For example, some may prefer to 1) use a genetic, structural biology or molecular biology approach to target identification/validation using information from genetic studies or studies of pathways, whereas others may prefer to 2) identify the function of a cellular target after first finding the target as a result of exploring binding patterns of natural products or other ligands to the novel target. The PA requires that the proposed target(s) in each application be novel and not addressed by drugs already approved for clinical use. This PA will expire on June 15, 2001 unless reissued. NIH Grants policies apply to these awards. RESEARCH OBJECTIVES Background The past 20 years have seen an explosion in the understanding of how cancer cells work. Increasing knowledge of human carcinogenesis is providing many new opportunities for study of molecular targets modulated by drugs that might prevent cancer. Most of the insights have resulted from an improved understanding of the genetic basis of carcinogenesis. Specific molecules have been identified which cause the initiation and progressive growth of tumors. From this work, a fundamental re-ordering of the approach to drug discovery and development for the treatment and prevention of cancer has emerged. There is the opportunity to move away from screening agents by their effects on tumor cell growth, in vivo or in vitro, and targets that have been thoroughly exploited. While it remains true that these methods might continue to be the basis for the development of clinically useful agents, these agents may not be the best lead compounds that effect a particular pathway of biologic importance specific for cancer establishment or progression. Drugs discovered by these early methods have historically demonstrated clear limitations in clinical efficacy. The hope is that drugs targeting new, specific molecular lesions in cancer cells will provide more selective and less toxic therapy or prevention approaches, alone or in combination with other agents. The focus of attention in this new approach to cancer drug discovery is a compound’s effect against a novel molecular target, or a target operating in a defined biochemical pathway, with the intent of causing a gain or loss in function to reverse, stop, or delay cancer progression. The cancer cell selectivity of lead compounds should be enhanced by screens based on a novel target or a critical pathway that represent a true Achilles heel. Some possible ways that preventive agents may modify molecular targets include interfering with tumor initiation by: 1) modifying carcinogen activation by enzymes responsible for activation or scavenging DNA reactive electrophiles or free radicals, 2) enhancing carcinogen detoxification processes by altering the activity of detoxifying enzymes, 3) repairing structural/functional genetic defects by enhancing endogenous DNA repair systems, 4) blocking tumor promotion and progression including altering the expression of genes involved in cell signaling, particularly those regulating cell proliferation, apoptosis and differentiation. The evaluation of drugs in the clinic which have emerged from these types of approaches is beginning. A recent example is the discovery of STI-571, a Novartis compound under investigation for the treatment of chronic myelogenous leukemia (CML) and other cancers. STI-571 has been shown by Schindler et al. in Science 289, 1938 (2000) to target the Bcr-Abl fusion protein, a tyrosine kinase whose expression is considered to be the cause of CML. Other examples which might be mentioned include the farnesyl transferase inhibitors (FTIs), protein kinase (PK) antagonists of various sorts, matrix metalloprotease inhibitors, and growth factor receptor or other effector antagonists (herceptin, endothelin, tamoxifen, TRAIL, etc.). Recent cancer epidemiology and pharmacogenetic studies have suggested the importance of genetic polymorphisms affecting the ability to detoxify carcinogens, e.g., glutathione-S-transferase (GSTM1, GSTM2, GSTP1), N-acetyltransferase (NAT1, NAT2), cytochrome P450 (CYP450IAI), and steroid 5-alpha-reductase type II (SRD5A2). It is striking that in this process the pharmaceutical industry has clearly seized a defining role in expeditiously advancing potentially useful compounds to a clinical test. However, in each of the instances cited, the pioneering studies on the targets to which these drugs are directed occurred largely (if not exclusively) in the academic sector. Objectives and Scope The goal of this PA is to provide the means for investigators to generate preliminary data leading to the discovery and validation of molecular targets for cancer prevention or treatment intervention which can be developed into drug discovery assays. Identification of a potential target might present varying degrees of difficulty, but validation (an indication of a target’s predictive capacity to aid in the selection of clinical drugs) is apt to be uniformly more problematic. Leads for many existing clinical drugs were not discovered through the use of macro-molecular targets but rather through in vivo or in vitro anti-proliferative assays. Accordingly, the cornerstone of this effort is the validation of targets of demonstrated importance. However, the exploratory/development grants, herein described, should be projects that seek preliminary data in the identification or validation of molecular targets or their development into a screening tool. Approaches and projects appropriate for this PA should be in one or more of three general areas as follows: First, investigative activities establishing a molecule as a potential cancer drug discovery target can have as its focus any aspect of early dysplasia or cancer cell biology that may reveal a vulnerability in the cancer cell. These might include cell cycle checkpoints, DNA repair, cell stress, cell immortalization or cell death pathways, cassettes of altered transcription factor activity, activation of pathways allowing cell growth in hypoxic or hypo-vascularized conditions, events involved in angiogenesis, cell invasion and metastases, or strategies to modulate the immune system. Oncogenic viral targets also would be appropriate. In fact, any difference between a cancer and normal cell could potentially be exploitable as a therapeutic maneuver. Modern science has afforded numerous opportunities to demonstrate the likely value of this approach. These include: (1) engineered animals of various sorts (transgene-expressing, knock-out, etc.), (2) smart assays designed to give information, not only about phenotypic alteration, such as growth arrest or cell death, but also about the effect on particular molecular targets of pathways known or suspected to have biological relevance to cancer, (3) array technology, where the action of a candidate drug lead against its target can be placed rapidly in the context of expected action against other cellular and indeed organ-specific molecules, and (4) cancer gene discovery programs, such as the Cancer Genome Anatomy Project (CGAP) (http://www.ncbi.nlm.nih.gov/CGAP/), which has identified numerous mutational sites in cancer cells, some of which are possibly unique to specific types of cancer. Accordingly, a requirement is to establish that a molecular target likely affects important aspects of cancer cell function. Second, the validation of new molecular targets, with the intent of discovering new agents for the treatment or prevention of cancer, is an important and necessary activity. At present, science appears to offer too many targets. Therefore, projects should focus on determining which of these numerous potential defects are sites of critical vulnerability which could be exploited for intervention. Ideally one would expect to demonstrate that manipulation of the target function would cause a phenotypic change in the cancer cell. Clearly if a prime target is fully validated, such that the target can be used to totally exploit a unique difference between a healthy and a cancerous cell, control of cancer would then only await the discovery of a drug molecule through a systematic screening and/or drug design program, in real laboratory experience, validation occurs in stages or degrees. Demonstration of some phenotypic or functional change that is desirable, such as elimination or reversal of dysplasia, tumor shrinkage or change in a validated surrogate marker, would provide evidence of the importance of a target. Approaches to target validation might involve the use of antisense or engineered animals, such as transgene-expressing or gene knock-outs. Small, bioactive molecules, obtained either from natural products libraries or from chemical libraries, may be used as ligands to select and validate proteins from arrays. If an investigator chooses to utilize crude extracts of natural products, as from the NCI Active Repository, expertise must be available for chemical fractionation of the extracts. Thus, validation can be conceptualized as a series of milestones. A proposal to reach validation milestones could be responsive to this PA. There are many good rationales for selecting targets, but validation requires considerable imagination and skill on the part of the investigator. Therefore, also responsive to this PA would be an insightful and clever validation of a target suggested by others as a possible intervention point. While it is true that the ultimate validation can only come from a successful clinical trial, having information on the importance of the target prior to the trial should provide important feedback in case therapies are ineffective. Third, the target system should be amenable to conversion into a screen for effectors of the target’s function (at minimum on a laboratory scale), or the molecular structure determined through biophysical techniques as a prelude to drug discovery studies . These aspects are critical components which would form the thrust of any molecularly focused drug discovery effort. The practical nature of drug discovery research is of high importance. While the desirability of this approach might seem obvious, the tools for accomplishing this task are only now becoming routinely available. These include sequence information defining the primary structure of relevant target proteins or other macromolecules, expression vectors for their large scale production, biophysical (e.g. X-ray and NMR) and computational techniques to allow the determination of three-dimensional structure, advances in screening technology to allow ever increasing speed and efficiency in assessing large numbers of candidate structures, and combinatorial chemistry to generate large numbers of candidate drug structures. SPECIAL REQUIREMENTS Patent Coverage. Since the discovery of new targets, assays and improved anticancer treatment and prevention is the objective of this effort, and since transfer of intellectual property to industrial laboratories for extended developmental purposes is facilitated by the existence of adequate patent coverage, it is essential that applicants provide plans to assure such coverage. Each applicant must therefore provide a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to P.L. 96-517 as amended by P.L. 98-620 and 37 CFR Part 401. Instructions were also published in the NIH Guide for Grants and Contracts, Vol. 19, No. 23, June 22, 1990. A formal statement of patent procedures and plan for transfer of materials embodying intellectual property to other parties as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, signed and dated by the organizational official authorized to enter into intellectual property arrangements for each applicant and collaborators, if any, must be developed. The signed agreement must be submitted prior to award to Dr. John A. Beisler at the address provided below under INQUIRIES. Applicants proposing to access the Natural Products Repository of the NCI must obtain and execute the Natural Products Repository Material Transfer Agreement (MTA) prior to receiving an award. Similarly, applicants proposing to access the synthetic repository of the NCI must obtain and execute the synthetic MTA prior to receiving an award. These agreement forms are available at http://dtp.nci.nih.gov. (On the panel, left side, click on "Organization", select "Natural Products Branch", select "Natural Products Repository", then scroll down to and select "Material Transfer Agreement"). For information concerning the NCI synthetic or natural product repositories go to the Developmental Therapeutics web site, http://dtp.nci.nih.gov (On the panel, left side, click on "Samples and Services"). For applications involving natural products, the applicant must provide a formal statement signed by an authorized representative of the applicant institution which assures that an equitable portion of royalties or profits arising from drugs discovered, if any, will benefit indigenous peoples, research collaborators, research institutions or governmental entities as appropriate, in the country of origin of the natural product sample from which the drug was derived. Plans for the procurement of proper collection and export permits must be provided. The signed document must be submitted prior to award to Dr. Gordon Cragg at the Developmental Therapeutics Program web site, http://dtp.nci.nih.gov (On the panel, left side, click on "Organization", select "Natural Products Branch" then click on "Organization/ Staff Directory"). A plan must be developed for disposition of natural products samples, chemical libraries, etc. The signed document must be submitted prior to award to Dr. John A. Beisler at the address provided below under INQUIRIES. The four documents listed above will not be included with review material, and therefore, will NOT be required at the time of application. However, awards will not be made until they are received and approved by NCI. MECHANISM OF SUPPORT The funding instrument to be used for these awards is the exploratory/developmental grant (R21). The R21 mechanism provides limited funds for short-term research projects, especially for generating preliminary data to establish a new, more comprehensive research study. The exploratory/developmental grant (R21) mechanism was designed to give resources to an investigator, who may then accumulative data to assess the feasibility of a line of research. Therefore, this is a preferred mechanism for projects that would clearly be premature for a traditional research project. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R21 application submitted in response to this PA may not exceed TWO years. Although 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, including Facilities and Administrative (F&A) costs awarded to the collaborating institution, in which case the limit is $125,000 in direct costs (five modules) per year. These grants are non-renewable and continuation of projects developed under this program must be through other grant mechanisms. The earliest anticipated award date is April 1, 2002. Although no funds for this PA will be used to support intramural projects, NIH intramural applicants must verify that the amount of the resources allocated from intramural sources does not exceed $100,000 in direct costs. For further budget information pertaining specifically to NIH intramural applications, see APPLICATION PROCEDURES below regarding ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS . 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 These exploratory/developmental grant applications (R21) 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. Domestic applications may include international components. Applications may also be submitted by an intramural laboratory from the National Institutes of Health. For this PA, NIH investigators may submit applications, but they may not request or receive funds from this program. 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 in cancer treatment to: John A. Beisler, Ph.D. Developmental Therapeutics Program National Cancer Institute EPN 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: beislerj@exchange.nih.gov Direct inquiries regarding programmatic issues in cancer prevention: Winfred F. Malone, Ph.D. Chemopreventative Agent Development Research Group National Cancer Institute EPN Room 200A 6130 Executive Boulevard Bethesda, MD 20892-7322 Rockville, MD 20852 (for express/courier service) Telephone: (301) 594-0460 FAX: (301) 402-0553 Email: malonew@mail.nih.gov Direct inquiries regarding fiscal matters to: Ms. Barbara A. Fisher Grants Administration Branch National Cancer Institute Executive Plaza South 243 Bethesda, MD 20892-7150 Telephone: (301) 846-1015 Fax: (301) 846-5720 Email: fisherb@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 May 17, 2001, a letter of intent that includes a descriptive title of the proposed research, name, address, and telephone number of the Principal Investigator, identities of other key personnel and participating institutions, and 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 subsequent application, the information that list contains allows NCI staff to estimate the potential review workload and plan the review. The Letter of Intent should be sent to Dr. John A. Beisler at the address listed under INQUIRIES. 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 applicant, reviewers and NCI 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. NIH intramural project applicants must follow the directions below under the section heading: ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS". 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 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 program contacts listed in INQUIRIES above 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 4 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 if applicable 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. 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. Provide an additional narrative budget justification for any year to year variation in the number of modules requested. 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 expedite the review process, at the time of submission, send two additional signed photocopies 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 express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt date at the beginning of this program announcement. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as a research project application 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 an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. SPECIAL INSTRUCTIONS FOR ALL APPLICANTS The PA title, MOLECULAR TARGET DRUG DISCOVERY FOR CANCER: EXPLORATORY GRANTS, and number of this PA must be typed on line 2 of the face page of the application form and the YES box must be marked. The plans below, if appropriate for the proposed work, should be included in the application after the LITERATURE CITED section. Formal agreements signed by an authorized representative of the applicant institution will be required before award. o A plan for patent coverage and licensing, for transfer of materials embodying intellectual property to other parties, for resolution of legal problems should they arise. o A plan for an assurance to return benefits to the country of origin in the use of natural products. o A plan for the disposition of natural products samples and chemical libraries. o A signed Materials Transfer Agreement (MTA) if products from the Natural Products Repository will be obtained. ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS The research grant application form PHS 398 (rev. 4/98) is also to be used by NIH intramural project applicants in applying for these grants. Applications kits 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 the PA must be typed on line 2 of the face page of the application form and the YES box must be marked. The 398 kit may also be found on the internet at http://grants.nih.gov/grants/funding/phs398/forms_toc.html. The PHS 398 application form should be used with the following modifications: o On the Face Page, fill out only items 1, 2, 3 (leave 3c blank), 4 and 5. The remainder of the items should be left blank, and the application must not be signed by either the PI or an NIH Institute official. o Do not submit "Other Support", Checklist", "Personnel Report", or "Personal Data" pages. o The PI must obtain the approval of the NIH Institute Scientific Director when applying as a principal investigator in the MTDD program under the terms and conditions of the PA. A copy of that letter of approval must be provided as part of a cover letter, addressed to the NCI Referral Officer, for the application. o The budget page should supply the time and effort for each project participant, but no other budget figures should be included. The resources available for the project and the research environment should be carefully described, but no budget figures should be included. The NIH Institute Scientific Director, as part of the letter of approval for participation, must verify that no more than $100,000 direct costs of intramural resources will be allocated to the project described in the application, and provide assurance that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. o For NIH intramural applicants, a letter of approval must be submitted from their Institute Intramural Scientific Director to allocate resources to the project. o Submit an unsigned, typewritten original of the application, and five photocopies to: Ms. Toby Friedberg Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8109, MSC 8239 Bethesda, MD 20892-8239 Rockville, MD 20852 (for express/courier service) Do not send the application or any copies to the Center for Scientific Review. NIH intramural project applications must be received by July 18, 2000. If an application is received after that date, it will be returned to the applicant without review. REVIEW CONSIDERATIONS: Upon receipt, applications will be reviewed for completeness by CSR 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 will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities of the NCI in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which 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 the 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-sponsored research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Within this framework, the specific goals of this PA are to provide support to enable investigators without preliminary data to discover and/or validate new molecular targets with the potential for developing assays for the discovery of new agents to treat or prevent cancer. For example, these exploratory/ developmental grants may be to identify or characterized (de novo, or from the literature) a target, to generate data for a validation, or to develop a method to render a validated target into a drug assay. Meritorious projects will include imaginative intervention points and insightful validation approaches, which overall will reveal an exploitable site of critical vulnerability. The reviewers will comment on the five criteria listed below in their written critiques of the applications 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? Is the proposed molecular target of importance to development and maintenance of the transformed phenotype? Is the target new and not one which has been the object of other evaluative studies? What is the likelihood that assays using this target will lead to a new class of agents for the prevention or treatment of cancer? 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 alternate tactics? How well has the applicant addressed the major goals of the PA: identification of a novel target, its validation as an intervention point, or assay development? What is the likelihood that a high-throughput screen can be developed with the target? Has the applicant designed an appropriate set of experiments to demonstrate a critical site of vulnerability in the cancer cell which can exploited for treatment or prevention? If crude natural product extracts are proposed, are strategies for compound isolation and identification adequate? If structural biology studies are proposed, are plans adequate for the production of materials and have appropriate collaborations been arranged? If screening is proposed, are data handling procedures adequate, and is the assay validated and appropriate for large- scale or high throughput use? 3. Innovation. Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the approaches advance the use of new, validated molecular targets for new drug discovery? 4. Investigator. Is the investigator appropriately trained and suited to carry out this work? Is the research 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 valuable collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of the proposed budget and duration, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the adequacy of plans for including children as appropriate for the scientific goals of the research, or justification for exclusion, the provisions of human and animal subjects, and the safety of the research environment. For intramural applications, all of the above applies except applications will not be reviewed for completeness by CSR, the proposed budget will not be reviewed by the review group. 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. SCHEDULE Letter of Intent Receipt: May 17, 2001 Application Receipt Date: June 14, 2001 Review by NCAB Advisory Board: February 2002 Earliest Anticipated Start Date: April 1, 2002 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 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 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, Molecular Target Drug Discovery for Cancer, is related to priority areas of human cancer treatment and prevention. 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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