NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY: SBIR/STTR INITIATIVE Release Date: November 25, 1998 PA NUMBER: PAR-99-020 P.T. National Cancer Institute Letter of Intent Receipt Dates: January 15, 1999 and September 15, 1999 Application Receipt Dates: February 19, 1999 and October 19, 1999 PURPOSE This Program Announcement (PA) encourages the use of non-mammalian organisms to discover new cancer therapies. The goal is to identify key genes, enzymatic activities, components of signaling pathways, or cellular processes which are altered in human cancer, as potential intervention points that could be used in the design of new cancer drugs. Projects could focus on validating inferences already drawn from comparative study of cancerous and normal cells, exploring promising leads from the nature of mutations known to be associated with cancer development, or testing hypotheses generated by the identification of new and unknown gene products such as those sequenced through the NCI's Cancer Genome Project (CGAP). For example, projects may include development of organisms in which genes in key pathways or processes are mutated or in which human transgenes are expressed to simulate changes known to occur in human cancers. These genetic manipulations could present a "proof of principle" or validation of the importance of the target genes to the development of cancer. Some examples of genes that are well studied in model organisms and known or strongly suspected of involvement in cancer include oncogenes, proto-oncogenes, some cell cycle and signal transduction genes, and DNA repair genes. Investigations in response to this PA should provide insight into which genes or gene products in cancer-relevant pathways are potential targets for human cancer treatment. Projects of a general nature not specifically related to new cancer target or drug discovery will not be considered responsive. A search for small molecule inhibitors through screening is appropriate. Although this PA is being issued by the NCI, the National Institute of General Medical Sciences (NIGMS) has an interest in supporting projects related to this topic. Studies of growth regulation, cell cycle control, or other basic studies that are not explicitly focused on tumor target cell systems may be assigned to NIGMS or another Institute. This PA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS (PHS 98-2) and the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH FOR SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS (PHS 98-3). All of the instructions within the omnibus solicitation apply with the following exceptions: -Special receipt dates -Initial review convened by the NCI Division of Extramural Activities -Additional review considerations. 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 PA, "Non-Mammalian Organisms as Models for Anticancer Drug Discovery: SBIR/STTR Initiative", 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 Eligibility requirements are described in the OMNIBUS SOLICITATIONS. Any small business concern, independently owned and operated by United States citizens or lawfully admitted permanent resident aliens, which is located in the United States and is organized for profit, may apply. MECHANISM OF SUPPORT Support for the PA is through the SBIR and STTR mechanisms which are set-aside programs. Applications can be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants: Phase II STTR (R42) or Phase II SBIR (R44) grants; or under the SBIR/STTR FAST-TRACK option as described in the OMNIBUS SOLICITATIONS. Phase II applications in response to this PAR will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II proposal must be a logical extension of the Phase I research. Information on the FAST-TRACK process and the OMNIBUS SOLICITATIONS are available at: http://www.nih.gov/grants/funding/sbir.htm Unless otherwise noted, all PHS grants policies apply. RESEARCH OBJECTIVES The goal of cancer therapy is to eliminate malignant cells while sparing normal cells. Current clinically important drugs act as cytotoxic agents by binding to or damaging DNA, altering cellular mechanisms, or binding to structural proteins such as tubulin causing disruption of cell function. Generally, they were discovered as anti-proliferative agents without specific consideration to site of action. Thus, as might be expected, they show significant toxicity to normal cells which limits their clinical usefulness. Targeting specific cell control elements that are mutated in tumor cells provides a new and potentially valuable approach to identify new and more selective agents to add to the cancer armamentarium. A vast array of mutated proteins, regulatory processes, and signaling pathways has been implicated in cancer genesis and progression. However, only a select few, such as ras farnesylation and various tyrosine protein kinases, have been approached for cancer drug discovery. Determining which in this multitude of alterations and mutations are sites of vulnerability and are thus of importance for intervention, as well as designing approaches to exploit these sites for cancer drug discovery, are clearly daunting tasks. Non-mammalian cells offer an extraordinary opportunity to evaluate the importance and vulnerability of these sites and to suggest which could be of importance for drug discovery. Key growth regulatory pathways among eukaryotic organisms demonstrate a striking similarity. Importantly, cancer gene homologs and functional pathways containing homologs are of importance in a wide variety of cells including those of non-mammalian origin. Although not always of identical importance in humans, common pathways or at least portions of such pathways could be considered to be "functional cassettes" performing similar tasks within cells or organisms. For this reason, non-mammalian organisms, which are easier to manipulate genetically, have been valuable in defining new pathways relevant to neoplasia and in identifying interactions among components of pathways as well as functional relationships among the pathways. For example, at least 100 genes have been identified in yeast which have been classified as "damage control elements" whose gene products are involved in functions such as DNA repair, cell cycle regulation, check point control, and spindle formation. Several have been shown to have homologs in human cells such as the MSH2 and MLH1 repair genes and the ATM ataxia-telangiectasia) cancer susceptibility gene. Likewise, C. elegans biology has defined several genes important to apoptotic pathways with clear homologs in humans. Drosophila have recently highlighted the importance of the sonic-hedge hop pathway, whose members include a gene inactivated in basal cell carcinoma. Xenopus and zebrafish are additional non-mammalian organisms whose biology is being actively studied and are known to contain homologs of cancer relevant proteins. Importantly, genomic sequences of non-mammalian organisms are known as in the case of yeast or are being determined at a rapid pace, thus providing a basis for delineating the complexities of signaling pathways and control functions. LETTER OF INTENT Prospective applicants are asked to submit, by the dates listed on the first page of this PA, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the PAR 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. The letter of intent is to be sent to Dr. George S. Johnson at the address listed under INQUIRIES. APPLICATION PROCEDURES OMNIBUS SOLICITATIONS for both the SBIR and STTR programs are available electronically through the NIH, Office of Extramural Research "Small Business Funding Opportunities" web site: http://www.nih.gov/grants/funding/sbir.htm. Hard copies, subject to availability, may be obtained from the PHS SBIR/STTR Solicitation Office, phone (301) 206-9385; FAX (301) 206-9722; email a2y@cu.nih.gov. Helpful information in preparation of the application can be obtained: http://www.nih.gov/grants/funding/sbirsttradvice.htm Applications in response to this PA are to be submitted on the grant application form PHS 6246-1 (1/98) for SBIR Phase I [http://www.nih.gov/grants/funding/sbir1/sbir.htm], PHS 6246-3 (1/98) for STTR Phase I [https://grants.nih.gov/grants/funding/sbirsttr1/index.htm], PHS 6246-2 (1/98) for SBIR Phase II [http://www.nih.gov/grants/funding/sbir2/index.htm], and PHS 6246-4 (1/98) for STTR Phase II [http:/www.nih.gov/grants/funding/sttr2/index.html]. The applications are also located in the back pages of the OMNIBUS SOLICITATIONS. Applications will be accepted on February 19, 1999 and October 19, 1999. The title and number of this PA must be typed in line 2 on the face page of the application. Potential applicants are encouraged to contact program staff for guidance and to read the advice and information on the web sites. However, responsibility for planning, direction, and execution of the proposed research will be solely that of the applicant. As stated in the MECHANISM OF SUPPORT section, applications may be submitted for Phase I alone (R41/43), or Phase II (R42/44) alone if there has been previous and successful Phase I support, or through the FAST TRACK mechanism. Application instructions specified in the OMNIBUS SOLICITATIONS for each mechanism must be followed. The normal level of support and period of time for a Phase I SBIR award is $100,000 and six months; for a Phase II SBIR award, $750,000 and two years. The normal level of support and period of time for a Phase I STTR award is $100,000 and one year; for a Phase II STTR award is $500,000 and two years. However, applicants may propose longer periods of time and greater amounts of funds if necessary for completion of the project. (See NIH Guide, February 12, 1998; http://www.nih.gov/grants/guide/notice-files/not98-014.html). Phase I, FAST TRACK applications must specify clear, measurable goals that should be achieved prior to Phase II funding. Failure to provide measurable goals and sufficient detail in the Phase II application may be sufficient reason for the peer review committee to exclude the Phase II application from consideration. Phase II applications submitted in response to this PA will only be accepted as continuations of previously funded Phase I grants. The Phase II proposal must be a logical extension of the Phase I research but not necessarily a Phase I supported in response to this PA. An additional requirement of the FAST TRACK mechanism is the commitment for funds and/or resources for commercialization of the product. The Commitment Appendix to the Phase II application must specify amount of funds and/or nature of resources that will be dedicated to activities directly related to the SBIR/STTR project and must describe those activities. If such commitment is from an investor or partner organization, a copy of the agreement or a letter describing the details of the agreement must be provided. The small business concern must also submit a concise Product Development Plan (limited to five pages) as an Appendix to the Phase II application addressing the four areas described in the instructions for FAST TRACK applications in the OMNIBUS SOLICITATIONS. The completed original application and one legible copy must be sent or delivered 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 one additional copy of the application to: Ms. Toby Friedberg Referral Officer National Cancer Institute 6130 Executive Boulevard, Room 636a Bethesda, MD 20892-7405 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by the receipt dates listed at the top of the first page of this PA. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by the Center for Scientific Review (CSR) for completeness and by the NCI for responsiveness. Applications not adhering to application instructions described above and those applications that are incomplete or non-responsive will be returned to the applicant without review. Applications will be reviewed for scientific and technical merit by an initial review group convened by the NCI Division of Extramural Activities, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only t hose applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed assigned a priority score, and receive a second level review by the National Cancer Advisory Board. Review Criteria Review criteria are as described in the OMNIBUS SOLICITATIONS: 1. The soundness and technical merit of the proposed approach. 2. The qualifications of the proposed Principal Investigator, supporting staff, and consultants. 3. The scientific, technical, or technological innovation of the proposed research. 4. The potential of the proposed research for commercial application. 5. The appropriateness of the budget requested. 6. The adequacy and suitability of the facilities and research environment. 7. Where appropriate, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects and/or (b) protecting against or minimizing any adverse effect on the environment. The Phase I application should specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II. Failure to provide clear, measurable goals may be sufficient reason for the study section to judge the application non-competitive. AWARD CRITERIA Applications will compete for available funds with all other approved SBIR and STTR applications. Funding decisions for Phase I or Phase II applications will be based on quality of the proposed project as determined by peer review, availability of funds, and program priority. FAST TRACK, Phase II applications may be funded following submission of the Phase I progress report and other documents necessary for continuation. Phase II applications will be selected for funding based on the initial priority score, NCI's assessment of the Phase I progress and determination that Phase I goals were achieved, the project's potential for commercial success, and the availability of funds. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: George S. Johnson, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 841 Bethesda, MD 20892-7456 Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: johnsong@exchange.nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathleen Shino National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 248 FAX: (301) 496-8601 Email: shinok@gab.nci.nih.gov Direct inquiries regarding review matters to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 - MSC7407 Bethesda, MD 20892-7407 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: friedbet@dea.nci.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395. 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 52 and 45 CFR Part 74 and part 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 and contract 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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