Full Text CA-97-006 CANCER DRUG DISCOVERY: DIVERSITY GENERATION AND SMART ASSAYS NIH GUIDE, Volume 26, Number 15, May 9, 1997 RFA: CA-97-006 P.T. 34 Keywords: Cancer/Carcinogenesis Chemistry, Organic Medicinal Chemistry Chemotherapeutic Agents Drug Design National Cancer Institute Letter of Intent Receipt Date: June 20, 1997 Application Receipt Date: August 22, 1997 PURPOSE The Developmental Therapeutics Program (DTP), Division of Cancer Treatment, Diagnosis and Centers (DCTDC), National Cancer Institute (NCI) invites Program Project grant applications (P01s) proposing innovative combinatorial approaches to the generation of structural diversity and smart assay development for cancer drug discovery (Nature, Supplement to Volume 384, Issue No. 6604, November 7, 1996). Applications responsive to this RFA will bring together chemists and biologists who will propose novel approaches to the discovery of compound classes potentially active against cancer. This initiative seeks to catalyze the formation of multidisciplinary teams for the discovery of new agents that will exploit opportunities presented by the rapidly advancing state of contemporary chemistry and biology. Participants may come from the same or different departments in the same academic institution, or from different institutions, or from (an) academic department(s) and industry. Approaches will include the application of synthetic combinatorial or biosynthetic approaches to generate libraries of novel structures. Conceivably both techniques might be utilized by different components of the same research group, and active products of the biosynthetic approach may serve as novel scaffolds for elaboration using combinatorial synthetic technology. In close association with the generation of compound libraries, applicants should also propose the development or application of novel assays directed at molecular events or targets important in the neoplastic process and suitable for assaying the compound libraries. Applicants may employ any biological system that is likely to be informative in the context of this initiative. Structures based on clinically-approved anticancer drugs will not be considered responsive to the RFA. Although it is recognized that drug discovery can be a long and arduous process involving many steps, including lead discovery, lead optimization, and evaluation of promising candidates in pharmacology, toxicology, formulation and other studies in an effort to identify the most promising candidates for development to clinical trial, NCI is prepared to assist any awardee in bringing promising therapeutic candidates to clinical trial through its Decision Network process (Edward A. Sausville, "Working with the National Cancer Institute", Anticancer Drug Development Guide: Practical Screening, Clinical Trial, and Approval edited by B. Teicher, Humana Press Inc., Totowa, NJ, 1997 - in press) (available from Dr. Wolpert listed under INQUIRIES). Industrial partners also may be interested in supporting developmental activities. The goal of this RFA is to identify and optimize lead structures. Drug development activities, such as large-scale production of an agent, are beyond the scope of the RFA. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Cancer Drug Discovery: Diversity Generation and Smart Assays, is related to the priority area of cancer. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit, and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications may not be submitted by foreign institutions; however, an application from a domestic institution may include foreign components as research projects or core activities, as defined below under MECHANISM OF SUPPORT. Applications may include participants from the same or different departments in the same institutions, or from different institutions, or from academic departments and industry. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply as Principal Investigators (PIs). MECHANISM OF SUPPORT Support for this program will be through the National Institutes of Health (NIH) program project grant (P01) mechanism. The applications should be constructed using the P01 application guidelines of the NCI, which are available from the NCI Referral Officer as described below under APPLICATION PROCEDURES. The P01 mechanism is designed to support multiple, interacting projects focused on a central theme. P01s must have a minimum of three projects and also may include cores. A core is a separately budgeted component of a P01 that provides essential facilities or services to two or more of the proposed research projects. A core may not count as one of the three research projects. Cost sharing arrangements with industry are encouraged, but detailed project descriptions must be provided even if no funds are requested for a project or core activity. P01s may support projects that are performed at multiple sites but coordinated by a single Principal Investigator at the grantee institution. PIs will be responsible for the planning, direction and execution of the proposed project. An award will be made only to the PI's institution. All activities will be coordinated through an administrative core located at the PI's institution. An administrative core is recommended, especially if multiple institutions are involved in the P01. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and will be reviewed according the customary peer review procedures. Except as otherwise stated in the RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publications No. (OASH) 90-50-000, revised April 1, 1994. FUNDS AVAILABLE The NCI has set aside $3.75 million total costs (direct plus facilities and administrative costs) for the first year of funding. The number of awards and level of support is dependent on the receipt of a sufficient number and diversity of applications with high scientific merit. Applicants may request up to $950,000 total costs (direct plus facilities and administrative costs) for year one with no more than a 3% per year increase for future years. Budget requests should be carefully justified and commensurate with the needs of the project. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the awards may vary. It is anticipated that four to five awards will be made for periods up to five years, with the earliest expected award date being April 1, 1998. Although this program is provided for in the financial plans of the NCI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Recent developments in chemistry and biology suggest possibilities for an entirely new vision for cancer drug discovery. The unprecedented power of chemical and biological combinatorial techniques have made it possible to generate impressive structural variation in the laboratory. At the same time the fast-paced identification of gene products, gene sequences, and pathways relevant to neoplasia enables the creation of novel assays for biological functions relevant to cancer. These should permit a much more informative exploration of "diversity space" than has been possible previously for biological activities with therapeutic implications. Implementation of such assays on a large scale is now much more practical by remarkable engineering advances in robotics, miniaturization, and information processing. NCI proposes the present initiative to create multidisciplinary teams for drug discovery featuring close collaboration between chemists and biologists to explore novel approaches that will take full advantage of the opportunities presented by scientific advances. For many years, there have been extensive programs for the acquisition of novel structures from both natural and synthetic sources and for testing extracts and compounds in in vivo and in vitro screens for antiproliferative activity. This approach has been productive and has, in fact, yielded most of the agents in the current armamentarium (platinum complexes, nucleoside analogs, antifolates, vinca alkaloids, taxanes and camptothecin derivatives). The current state of the relevant science and technology suggests now, however, that a very different paradigm for the discovery of anticancer agents might be at hand. It seems clear, for example, that a vast diversity of chemical structures can be generated in the laboratory over surprisingly short time frames. There is no consensus at present that the degree of diversity derivable from laboratory experiments yet approximates what can be found in nature, but experience to date suggests that many millions of distinct structures can result from synthetic efforts extending over only a few months. In a similarly revolutionary vein, assays for biological relevance can now be designed to give information not only about phenotypic alteration, such as growth arrest or cell death, but about the effect on particular molecular targets of pathways known or suspected to have biological relevance to cancer. Research Goals and Scope Structural diversity may be generated by a variety of approaches, including combinatorial or parallel synthesis, or by genetic manipulation of biosynthetic pathways in producer organisms. The molecules produced may represent de novo collections of novel structures, or efforts to optimize lead structures with promising but incompletely developed potential. In no case should the compounds to be studied represent iterations of structures already FDA-approved for use in the treatment of human malignancy. Combinatorial Organic Synthesis: A key feature of combinatorial techniques is that compound synthesis can be designed such that a range of structures can be produced simultaneously as mixtures in the same reaction vessel or individually in parallel using semi- automated synthesis. The repetitive nature of the synthetic processes involved in most combinatorial applications lends itself to automation or semi-automation. This key feature means that the bench chemist can singlehandedly prepare tens, hundreds, or thousands of compounds of known structures in the time that it would take to prepare only a few pure entities by orthodox methodology. Combinatorial technology can be practiced in either a solution or solid-phase format. Solution techniques utilize methods essentially similar to standard methods for the synthesis of single compounds, except that instead of utilizing one well-defined reaction partner of each type per reaction, mixtures of several known reaction partners are utilized as building blocks, thus resulting in mixtures of analogs. The type of the chosen chemical reaction and the number of reactants depend on the nature of the desired structures. These mixtures may not be purified elaborately but are directly subjected to screening against the desired target (e.g., receptor, enzyme, antibody, cell). The chemistry is then repeated a few times in batches using different but well defined mixtures of reaction partners, and the products isolated and screened. In order to identify the leads, the chemistry is repeated several times using fewer reaction partners in each run, and the products are screened. This deconvolution process is repeated until the most potent lead is identified. In solid-phase approaches, pin or bead techniques permit the synthesis of different molecules on each pin (i.e., "one molecule- one bead"). The products of solid-phase synthesis can be cleaved from the backbone matrix for solution screening (which is essential when the screening target is a cell), or the most active molecules displayed on the polymer surface may be detected using molecular targets (receptor, enzyme, antibody) pre-tagged with a means of detection (visible color, fluorescence, radioactivity, chromophore, etc.) and then isolated and identified. Manipulation of Biosynthetic Pathways: Biosynthetic approaches to generating diversity may also be used to produce large numbers of novel structures. Recent progress has focused on the creation of hybrid antibiotics through genetic engineering (Katz et al., Ann. Rev. Microbiol 47: 875-912, 1993) and in the production of novel structures based on genetic manipulation of the aromatic polyketide biosynthesis pathways in prokaryotic microorganisms (Khosla et al., Nature 375: 549-554, 1995). A set of programming rules, which helps to predict the potential structures of novel polyketides produced by strains carrying these recombinants, has begun to emerge and forms the basis for the use of biosynthesis as a route to new aromatic polyketides. Polyketides are described in biosynthetic rather than structural terms. Broadly, this category comprises structures derived wholly or partly from poly- -ketomethylene chains, and includes a rich source of bioactive molecules, including antibiotics, such as the tetracyclines, anticancer agents, such as daunomycin, and immunosuppressants, such as FK506 and rapamycin. Outside the polyketide area there is still much to be learned in elucidating the biosynthetic pathways of secondary metabolites from other microbes, plants, or marine organisms. The exploration of biosynthetic pathways in plants and marine organisms has been much more difficult than that of their prokaryotic counterparts because of slower growth rates, the often more complicated structures of the secondary metabolites, the existence of multi-gene pathways that are not clustered in the genome, and the presence of enzyme-inactivating constituents. Definition of the pathways involved in the production of non-polyketide-derived structures especially by employing cell culture and modern molecular biologic techniques may also be tied to the generation of structural diversity. Applications which define and manipulate biosynthetic pathways but do not address the generation of chemical diversity will not be considered responsive to this RFA. Novel Screening Approaches: "Smart" assays may be operationally defined as a screening system that by its very operation conveys information about new chemistry or biology of "hits" in the system. For example, assays of interest to promote may couple the use of a cloned and expressed target protein or a nucleic acid sequence in tandem with a chemical or biosynthetic process that generates molecules for further study. Alternatively, the use of genetically definable yet underexplored organisms such as yeast, Drosophila, or C. elegans, production of expression vectors that may operate only in the presence of a compound with the desired properties, development of detection techniques based on novel patterns of molecular recognition, or strategies that require the operation of a particular molecular target to be a basis for detection would all examples clearly responsive to the RFA. SPECIAL REQUIREMENTS This initiative invites grant applications to support the assembly of inter-disciplinary teams with the skills needed to pursue successfully the generation of novel structures, their screening against defined biological or biochemical target(s), and the optimization of lead structures. The NCI recognizes that source countries retain interests in samples collected in their domains. All applicants who propose to use organisms or other naturally-derived materials of foreign origin in their studies must provide a plan, signed by representatives of all participating institutions, for equitable return of a portion of any profits or royalties, or other acceptable forms of compensation, derived from their discoveries to indigenous peoples, research collaborators, cooperating institutions or Governmental entities in the countries of origin, as appropriate to their contributions. It is preferred that this plan be submitted with the application. If this plan is not included as part of the application, it must be submitted as a condition for award to a Program Official to be designated at the time of award. Since the discovery of new anticancer agents may result from these P01 projects, it is essential that applicants provide plans to assure patent coverage. The situation could be complicated since multiple institutions, including industry, may be involved. 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. NOTE: A formal statement of Patent Agreement among participants and their institutions, 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 patent arrangements for each participant and participating institution is preferred with the application. If this signed agreement is not included in the application, it must be submitted as a condition for award to a Program Official to be designated at the time of award. 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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. LETTER OF INTENT Prospective applicants are asked to submit, by June 20, 1997, a letter of intent that includes a descriptive title of the proposed research and a list of titles for the anticipated components of the P01, 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 RFA 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 avoid conflict of interest in the review. Applicants requesting budgets greater than $500,000 total costs in any year of their proposed application are required to contact NCI program staff prior to submitting their applications (NIH GUIDE, Volume 25, Number 14, May 3, 1996). Applications with budgets of more than $500,000 received without prior communication with at least one of the NCI program staff listed under INQUIRIES will not be accepted for review. The letter of intent should be sent to the Referral Officer, National Cancer Institute at the address listed under APPLICATION PROCEDURES. APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (revised 5/95) in conformance with the P01 application guidelines of the NCI (revised 1995), which are available from the NCI Referral Officer, Division of Extramural Activities, National Cancer Institute Executive Plaza North, Room 636A, 6130 EXECUTIVE BLVD MSC 7405, BETHESDA, MD 20892 (Telephone: 301-496-3428, FAX: 301-402-0275, Email: [email protected]). PHS 398 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, Email: [email protected]. The RFA label available in the PHS 398 (revised 5/95) application form must be affixed to the bottom of the face page of the application such that it may not reach the review committee in time for review. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the title and number of the RFA must be typed on line 2 of the face page of the application and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040, MSC 7710 BETHESDA, MD 20892-7710 NORTH BETHESDA, MD 20817 (for express/courier service) In addition, at the time of submission, send two complete copies under separate cover to: REFERRAL OFFICER NATIONAL CANCER INSTITUTE 6130 EXECUTIVE BOULEVARD, Room 636A MSC 7405 BETHESDA, MD 20892-7405 (or ROCKVILLE, MD 20852 for overnight mail service.) Telephone: 301-496-3428 FAX: 301-402-0275 The deadline for submission of applications will be August 22, 1997. Late applications will not be accepted. If an application is received after the due date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the Division of Research Grants and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. If NCI staff find that the application is not responsive to the RFA, it will be returned to the PI without further consideration. The PI may submit the application as an unsolicited, investigator-initiated P01 at the next deadline for competing P01 applications. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Review Logistics Branch of the Division of Extramural Activities of NCI. As part of the initial merit review, all applicants will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level of review by the National Cancer Advisory Board. Because of the time allotted for the review, no site visits are planned. Therefore, it is important that all information necessary for an informed review be included in the written application by the due date. The Scientific Review Administrator (SRA) will contact the PI for the opportunity to provide supplementary material, such as recent publications, before the review. No material should be submitted unsolicited. The initial review group will also examine the provisions for the protection of human and animal subjects, if any, and the safety of the research environment. In addition to the standard Review Criteria used to evaluate P01 applications (as described in the P01 Guidelines), the following Review Criteria will be used to assess the scientific merit of each application: o scientific and technical merit and originality of the proposed research plans; o appropriateness and adequacy of the experimental approach, including the design strategies for combinatorial synthesis or biosynthesis of new leads; novelty and suitability of screens for the discovery of lead structures; optimization strategy; o relevance of screens to the neoplastic process; o decision-making process in identifying leads for optimization; o plans for data storage and manipulation; o evidence of research plans encompassing inter-disciplinary collaboration and coordination addressing the goals of generation of novel structures not based on clinically-approved anti-cancer drugs, the screening of novel structures against defined biological or biochemical target(s), and the optimization of lead structures; o adequacy of the scientific disciplines and specific competencies represented by the Principal Investigator and Project Leaders; research experience, competence, commitment, and time availability of Principal Investigator, Project Leaders, and other key personnel; o leadership, scientific ability, and administrative experience and competence of the Principal Investigator in the development, implementation, and management of comprehensive, inter-disciplinary research programs; o adequacy of plans for effective team communication and coordination; o evidence of the approval and commitment of institutions represented by team members to project goals, and the availability and adequacy of the existing physical facilities and resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; AWARD CRITERIA The earliest date of award is April 1, 1998. The following will be considered in making funding decisions: o Scientific merit as determined by peer review o Diversity of applications and programmatic priorities o Availability of funds o Responsiveness to the goals and objectives of the RFA. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Biosynthetic Issues Gordon M. Cragg, Ph.D. Natural Products Branch, Developmental Therapeutics Program Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute-FCRDC Fairview Center, Suite 206 P.O. Box B Frederick, MD 21702-1201 Telephone: (301) 846-5387 FAX: (301) 846-6178 Email: [email protected] Chemistry Issues Ven Narayanan, Ph.D. Drug Synthesis and Chemistry Branch Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 831 6130 Executive Boulevard, MSC 7448 Bethesda, MD 20892-7448 Telephone: (301) 496-8795 FAX: (301) 480-4817 Email: [email protected] Screening Issues George S. Johnson, Ph.D. Grants and Contracts Operations Branch Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 841 6130 Executive Boulevard, MSC 7456 Bethesda, MD 20892-7456 Telephone: (301)-496-8783 FAX: (301)-402-5200 Email: [email protected] Program Issues Mary K. Wolpert, Ph.D. Grants and Contracts Operations Branch Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute Executive Plaza North, Room 841 6130 Executive Boulevard, MSC 7456 Bethesda, MD 20892-7456 Telephone: (301)-496-8783 FAX: (301)-402-5200 Email: [email protected] Direct inquiries regarding fiscal matters to: Ms. Cynthia W. Mead Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 6120 Executive Boulevard, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 228 FAX: (301) 496-8601 Email: [email protected] 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 the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR Parts 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 Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. 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. .
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