THERAPEUTIC MODULATION OF ANGIOGENESIS IN DISEASE Release Date: July 30, 1998 PA NUMBER: PAR-98-096 P.T. National Cancer Institute National Heart, Lung, and Blood Institute National Eye Institute Letter of Intent Receipt Dates: October 15, 1998 and June 15, 1999 Application Receipt Dates: November 19, 1998 and July 20, 1999 PURPOSE This Program Announcement (PA) reflects the interests of the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Eye Institute (NEI) to encourage the translation of basic knowledge of the angiogenic process into therapeutic applications. It may also promote new collaborations between basic and clinical scientists currently engaged in this area of research to design novel therapeutic approaches to disease. This PA is for new grant applications focusing on vascular biology in disease pathogenesis and treatment. Projects ranging from pre-clinical studies in appropriate biological systems or models to design of pilot clinical applications are encouraged. The research could involve the testing of known pro- or anti- angiogenic agents to determine optimal therapeutic strategies for specific pathologies, to the development of animal models of particular diseases that might more accurately predict the human response to treatment with modulators of angiogenesis. 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, Therapeutic Modulation of Angiogenesis in Disease, is related to the priority areas of cancer and vascular disease. 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 foreign and domestic, public and private, for-profit and non-profit organizations, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Mechanisms available for support of this program are the research project grant (R01) and the exploratory/developmental grant (R21). R01s may include requests for up to five years of support and have no direct cost cap. The R21 mechanism provides limited funds for short-term research projects, especially for generating preliminary data to establish and validate a new, more comprehensive research study. R21 budget requests submitted to this PA may not exceed $100,000 in direct costs in any year, not including indirect costs awarded to a collaborating institution, and are limited to a total of two years. These grants are non-renewable and continuation of projects developed under this program must be through other grant mechanisms. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 94-50,000 (Rev.) April 1, 1994. Applicants who intend to submit a budget greater than $500,000 direct costs are required to contact the appropriate program staff before submitting the grant. RESEARCH OBJECTIVES Cancer and cardiovascular disease, two entirely different diseases, account for nearly three-quarters of all deaths in the U.S. New strategies for treating these diseases are beginning to emerge that are surprisingly similar, and involve regulating angiogenesis, the process by which new blood vessels arise as outgrowths of existing vessels. In addition to these potentially fatal diseases, other less life-threatening diseases involving uncontrolled angiogenesis, for example neovascular eye diseases causing blindness, may also be amenable to this type of treatment. Therefore, controlling the angiogenic process may prove effective as a treatment paradigm for a wide range of cardiovascular and pulmonary diseases, for inhibiting tumor growth and metastasis, and for preventing and treating certain eye diseases. Because regulation of blood vessel growth is of paramount importance in many diseases, research designed to understand the biology of angiogenesis is broadly supported throughout the National Institutes of Health. The results of this research have been very successful in establishing a solid foundation of information about the factors involved in promotion, maintenance, modulation, and inhibition of growth of the vascular system. It is now imperative that the successes of basic biology be transmitted rapidly into pre-clinical and clinical research programs for the prevention and treatment of diseases of the heart, vasculature, lung and eye, and cancer. I. The NCI has not previously targeted angiogenesis research as a special priority, however it has become a field of immense opportunity because of the acceleration of developments that demonstrate the profound dependence of tumor growth and metastasis on the generation of new blood vessels. The results of this research have gone beyond the initial promise of understanding the regulation of vascular growth to the creation of a new era of cancer therapy utilizing angiogenesis inhibitors to limit or completely control malignancy. Recommendations from recent workshops and meetings have further demonstrated that the NCI has a responsibility to help transmit the successes of basic biology into pre-clinical and clinical research programs as rapidly as possible. Numerous strategies have been proposed for blocking angiogenesis, including targeting the growth factors that stimulate endothelial cell proliferation or blocking their receptors on those cells, preventing the assembly of endothelial cells into functional vessels, increasing the available levels of endogenous inhibitors of angiogenesis, or administering synthetic inhibitors alone or in combination with chemotherapeutic drugs to patients. II. The NHLBI has an interest in both the promotion and inhibition of angiogenesis. Inappropriate angiogenesis is involved in deleterious remodeling in atherosclerosis and restenosis, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, and asthma. Thus, as with cancer therapy, development of anti-angiogenic agents will be an important area of cardiovascular and pulmonary disease research. However, stimulation of angiogenesis is also important in certain other heart and vascular diseases. As the NHLBI celebrates its Fiftieth Anniversary, discoveries from basic research on angiogenesis are just beginning to be translated to the clinical arena as new treatment modalities for ischemic heart and peripheral vascular disease. Through the use of recombinant protein and gene therapeutic approaches, pro-angiogenic agents such as Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor (FGF) have been introduced into humans and new blood vessel growth in the legs and hearts of patients has been achieved. Most importantly, a clinically favorable outcome has been seen in some instances. Thus, therapeutic angiogenesis may help to reduce the need for limb amputation in patients with peripheral vascular disease, and in the case of revascularizing the heart, could potentially augment or even replace bypass surgery. The NHLBI is interested in furthering the translation of basic research in angiogenesis to the pre-clinical and clinical arenas. We encourage collaborative efforts among basic scientists, clinicians, and industry to develop research on pro/anti-angiogenic agents and targeted drug delivery systems for cardiovascular and pulmonary diseases, and coagulation disorders which may lead to new strategies for preventing and reversing angiogenic remodeling or stimulating angiogenesis depending on the disease and intent. III. The NEI supports research on diseases of the retinal and choroidal vascular system which are major causes of visual disability and blindness. Pathological angiogenesis from retinal and choroidal circulations may be a serious consequence of many eye diseases. Retinal neovascularization occurs in diabetic retinopathy, sickle cell retinopathy, retinal vein occlusion, and retinopathy of prematurity (ROP). Occlusion of the central retinal vein, or one of its branches, can lead to rapid diminution of vision with later sequelae of retinal neovascularization. The vascular supply to the optic nerve, derived from the choroidal system, may be interrupted in anterior ischemic optic neuropathy. New blood vessels arising from choroidal capillaries lead to choroidal neovascularization which occurs in age-related macular degeneration and several macular diseases. Despite the prevalence of these diseases, many of the molecular and cellular events surrounding abnormal angiogenesis in the eye are not understood. The NEI and the National Advisory Eye Council have identified research on abnormal angiogenesis in the eye as a priority in Vision Research, A National Plan: 1999-2003. The NEI is interested in supporting research on angiogenesis, especially as it relates to diabetic retinopathy, neovascular macular degeneration, ROP, and neovascular glaucoma (a sequel of both central retinal vein occlusion and proliferative diabetic retinopathy). Vascular endothelial growth factor (VEGF)/Vascular Permeability Factor (VPF) has been identified as a possible agent in retinal neovascularization. Studies show that expression of VEGF is stimulated by a lack of oxygen or hypoxia. Dramatically elevated levels of VEGF are observed within the eyes of patients with diabetic retinopathy. This suggests that pharmacologic intervention in diabetic retinopathy may be possible and discovery of agents that prevent or retard retinal and/or choroidal neovascularization is an important research priority. Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) appear to be associated with proliferative stages of diabetic retinopathy. Transgenic mice are being used to study the role of GH and IGF-1 in ischemia-induced retinal neovascularization, and their interaction with VEGF. Studies suggest that systemic inhibition of GH or IGF-1, or both, may have therapeutic potential in preventing some forms of retinopathy. The following are examples of the types of research that NCI, NHLBI, and NEI would support under this program announcement, other areas may also be appropriate in view of the type of research that is being requested: Studies to determine the best candidates for inducing or inhibiting angiogenesis in specific pathologies. These could include the use of cytokines, growth factors, growth factor receptors, receptor antibodies, soluble receptors, adhesion molecules, coagulation factors, proteases, protease inhibitors, peptides, and other small molecules. In addition, studies using these agents in combination to identify optimal therapeutic strategies are encouraged. Development of animal models of particular diseases to identify the system that would most accurately predict the human response to a pro- or anti-angiogenic agent to treat a specific disease. Development of optimal in vivo delivery systems for pro- or anti-angiogenic agents in animal models, for example, naked DNA vs. adenoviral delivery of genes, bolus vs. sustained release of recombinant proteins, intravascular vs. local routes of delivery. Development of fast and effective methods for screening angiogenic stimulators and inhibitors preclinically. New techniques to upregulate the endogenous expression of, or to express through gene therapy or other molecular strategies, anti-angiogenic or pro-angiogenic agents that act directly on the target tissue of interest (e.g., endothelial cells in tumor blood vessels). Establishment of diagnostic standards for the assessment of angiogenesis. For example, physiological parameters, morphological and/or cellular endpoints. Studies to determine the existence of, and role for, circulating endothelial stem cells in new blood vessel growth and to design strategies that could interfere with this cell reserve. Additional areas of special interest to the NCI include: Identification and clinical development of compounds designed to target unique surface molecules specific to the endothelial cells in tumor vessels of specific organs. Such compounds might be tethered to toxic drugs that would then be directed to that tumor vasculature to destroy it and the surrounding tumor cells. Identification and clinical development and exploitation of anti-angiogenic agents effective against the endothelial cells in the atypical neovasculature in tumors but not normal vessels. Investigation of other cell receptors and genes that may be involved in tumor- associated angiogenesis. Additional areas of special interest to the NHLBI include: Systematic testing of the relative benefit of recombinant protein infusion vs. gene transfer approaches to treatment of cardiovascular and lung diseases, and disorders of coagulation. Development of non-invasive methods to maximize the body’s ability to develop collateral vessels. 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and 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. NIH POLICY AND GUIDELINES ON THE 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: LETTER OF INTENT Applicants are requested to submit a letter of intent to respond to this PA and may suggest an Institute assignment for their grant. The letter should include the names of the principal investigator and collaborators, a descriptive title of the proposed research, and the number and title of this PA. There are two dates for submitting applications to this solicitation, November 19, 1998 and July 20, 1999. Each date is preceded by a due date for submitting a letter of intent, October 15, 1998 and June 15, 1999, respectively. Letters of intent may be sent to Colette S. Freeman, Ph.D. at the address listed under INQUIRIES APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). 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 301/435-0714, E-mail: The number and title of the program announcement must be typed in Section 2 on the face page of the application and the YES box must be checked. The PHS 398 application is also available on the Internet at: The completed original application and four legible copies 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) One copy of the application must be sent or delivered to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard - Room 636A Bethesda, MD 20892-7407 Rockville, MD 20852-7407 (for express/courier service) REVIEW CONSIDERATIONS Applications will be screened for responsiveness to the purpose of this program announcement and those judged non-responsive will be referred back to Center for Scientific Review (CSR) for review in an appropriate CSR study section. Applications will initially be assigned to the NCI with dual assignment to NHLBI and NEI. Final primary Institute assignment will be determined by CSR on the basis of established PHS referral guidelines and Institute/Program relevance. Applications will be reviewed for scientific and technical merit by a Special Emphasis Panel convened by the Division of Extramural Activities of the NCI, in accordance with the standard NIH peer review procedures. Following scientific merit review, the applications will receive a second-level review by the appropriate national advisory council(s). As part of the initial merit review, 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of the proposed project budget and duration, the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priorities. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Colette S. Freeman, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 505 Bethesda, MD 20892-7385 Telephone: (301) 496-7028 FAX: (301) 402-1037 Email: Stephen S. Goldman, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 10193 Bethesda, MD 20892-7956 Telephone: (301) 435-0565 FAX: (301) 480-2858 Email: Peter Dudley, Ph.D. Division of Extramural Research National Eye Institute 6120 Executive Boulevard, Room 350 Bethesda, MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: Direct inquiries regarding fiscal matters to: Priscilla Grant Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, Ext. 245 FAX: (301) 496-8601 Email: Direct inquiries regarding review issues to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636A Bethesda, MD 20892-7407 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Numbers 93.396, 93.837, 93.838, 93.839, and 93.867. 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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