Full Text HL-94-014 ANGIOGENESIS IN BREAST CANCER NIH GUIDE, Volume 23, Number 17, May 6, 1994 RFA: HL-94-014 P.T. 34 Keywords: 0715036 Cardiovascular Diseases National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: August 1, 1994 Application Receipt Date: September 13, 1994 PURPOSE The Division of Heart and Vascular Diseases invites research grant applications for up to four years of support for research into breast cancer angiogenesis. The objective of this Request for Application is to encourage vascular biologists to apply their knowledge and skills to elucidate the mechanisms where by breast tumor cells stimulate angiogenesis and control the structure and function of the tumor blood vessels. The ultimate goal is to identify strategies that offer possibilities for treating breast cancer by inhibiting the vascularization of tumors. 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 RFA, Angiogenesis in Breast Cancer, 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 (202-783-3238). Trans-NIH Breast Cancer Collaborative Effort This RFA is part of the activities to be initiated by the National Institutes of Health (NIH) to advance knowledge regarding the etiology, treatment, and prevention of breast cancer. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for applications submitted in response to this RFA may not exceed four years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE Approximately $1.5 million in total costs will be provided for the first year of support for the entire program. It is anticipated that no more than eight grants will be awarded under this program. This level of support is dependent upon the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plan of the NHLBI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Administrative adjustments in project period and/or amount of support may be required at the time of the award. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. RESEARCH OBJECTIVES Background The average U.S. mortality rate for breast cancer is 27.5 per hundred thousand women. Approximately 46,000 women died of breast cancer in 1993. Thus, despite vigorous efforts to diagnose, treat and prevent this disease, it remains a leading cause of death among women. In order to develop new approaches to the treatment of this disease, further knowledge is needed of the basic biology underlying the etiology and progression of the disease. The orientation of this RFA is on the mechanisms whereby cancer tumor cells promote angiogenesis as a means of providing nutrients to the tumor cells and a conduit for escape of tumor cells into the circulation. Recent studies have shown that vascularization is significantly higher in node-positive breast tumors than in node-negative tumors, and that a high degree of vascularization is generally associated with a poorer prognosis. This finding has led to the conclusion that inhibition of angiogenesis offers a possible therapeutic modality for a subset of patients. Circulation in a tumor has both favorable and detrimental aspects. The existence of blood vessels provides for the delivery of antitumor therapeutic agents but at the same time it provides an escape route for metastases. In a growing tumor, pre-existing host blood vessels become incorporated into the tumor tissue. These vessels, however,are altered; venules are tortuous, elongated and dilated. New blood vessel growth occurs from these venules or from venules in the host tissue adjacent to the invasion front. Some of the original host vessels in the tumor disintegrate, are obstructed or are compressed. Of the remaining vessels, arteries seem to become permanently dilated and resistant to the invasive and destructive growth of tumor cells. The newly formed vessels randomly fuse either with arterioles or venules and create a microcirculation that has many characteristics not found in the microcirculation of normal tissues. These characteristics include abnormal morphology,absence of vasomotion, increased fragility, and increased permeability. Regions of a tumor may be avascular or poorly vascularized and it is unclear why angiogenesis fails in those regions. A fundamental question that remains unanswered is how angiogenesis is initiated in an avascular tumor. In the heart, the stimulus is thought to be ischemia and the vascular response is almost immediate. Animal models subjected to embolization showed evidence of angiogenesis in three days. Tumors can remain avascular and survive by growth at the periphery and necrosis at the center for several years before angiogenesis begins. On the other hand, some breast tumors metastasize before they are clinically detectable and it is not clear whether or not angiogenesis is a very early event in these cases. Investigations into the process by which tumor cells may switch to the angiogenic phenotype include the following mechanisms: (1) basic fibroblast growth factor (bFGF) normally confined within cells or bound in the extracellular matrix is reported to be released when tumor cells become angiogenic and (2) angiogenic inhibitors secreted by cells decrease with the onset of angiogenesis presumably due to a loss of a tumor suppressor. The mechanism may be tumor specific, and it is important to know whether these or other mechanisms stimulate angiogenesis in breast cancer. The first apparent response to an angiogenic stimulus from a tumor is thought to be dissolution of the basement membrane surrounding a pre-existing vessel, usually a post-capillary venule. Endothelial cells are then believed to migrate toward the tumor. The leading endothelial cells do not appear to divide, whereas those behind do. After elongation of immature vessels, lumen formation occurs along with branching and formation of vascular loops to produce a vascular network. Finally, capillaries become surrounded by basement membrane components and, in most cases, pericytes. However, as described in further detail below, these processes differ from those seen in vascularization of normal tissue. The question of how these events are effected is complex but it is clearly the result of interactions, either direct or indirect, between tumor cells and endothelial cells. Much progress has been made in identifying factors that contribute to tumor angiogenesis. In fact, more than a dozen purified molecules have been shown to be angiogenic; most of them are polypeptides, but lipids, nucleotides, copper, selenium, and one vitamin have also been shown to have angiogenic properties. The more difficult task is to now develop an understanding of the cascade of events that result in vascularization of a breast tumor and to identify specific factors and their precise roles in that process. Some of these factors are angiogenic in vivo but do not have measurable effects on cultured cells, probably because the effect requires the presence of other cells, such as macrophages that produce endothelial activating factors, or because the factor is normally stored in a cell or the extracellular matrix and is only released under certain conditions. Angiogenin is one factor that has no effect on endothelial cell cultures. Additionally, it is produced in adult rat liver and is found in normal bovine and human plasma. Thus, its activity as an angiogenic factor seems to be expressed only in special circumstances when a receptor is presented on the endothelial cell surface. Some factors such as angiotropin, fibrin, and tumor necrosis factor-alpha (TNF-alpha) stimulate endothelial cells to migrate, but not to proliferate. Others, such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are both mitogenic and chemotactic. Mitogenic factors can be produced by macrophages, monocytes, platelets, and lymphocytes as well as tumor cells. Heparin-binding growth factors (HBGFs), including basic and acidic FGFs, do not have signal peptides, yet appear to be released into the subendothelial extracellular matrix and stored there bound to heparin sulfate. Degradation of the extracellular matrix is, in itself, a complex process involving T and B lymphocytes, platelets, granulocytes, macrophages, mast cells, and endothelial cells, as well as compounds such as thrombin, and plasminogen activator (PA). PA inhibitors (PAIs) are also present. Degradation appears to be under the control of tumor cells. A further step needed for the potent mitogens to interact with endothelial cells is the expression of receptors on those cells. How all of these steps are integrated is not well understood. Ischemia/hypoxia is reported to be a stimulus for angiogenesis. Recent studies have shown that VEGF is highly expressed in human gliomas around the periphery of necrotic cords and that the VEGF receptor is expressed only on endothelial cells. In culture, a glioma cell line was shown to express VEGF mRNA in response to hypoxia. Upon reoxygenation, mRNA levels returned to control levels. Since VEGF expression is also influenced by estrogen, there may be a particular relevance to breast cancer. Other participants in the angiogenic process are circulating cells recruited to tumor sites. These include neutrophils, monocytes, macrophages, lymphocytes, eosinophils, basophils, and mast cells. Their specific roles are only partially understood. Of these cells, only macrophages appear to have the ability to stimulate angiogenesis alone. Mast cells may play a role in the initiation of angiogenesis but this possibility remains to be elucidated. Heparin released from mast cells is thought to have a role in potentiating angiogenesis but not to be able act alone. Moreover, in other circumstances, heparin appears to be antiangiogenic. It is important to note that the roles of angiogenic factors in tumor vascularization may differ from those in wound healing. There are important distinctions between the structure and function of tumor versus normal endothelium. Thus, once the process of angiogenesis is initiated, tumor cell-endothelial cell interactions become determinants of the growth, morphology, and function of the developing vessels. For example, normal capillaries are often surrounded by pericytes, whereas these may be reduced in number or absent from tumor capillaries. Pericytes are thought to be involved in the maturation of vessels and the inhibition of endothelial proliferation. The combined activity of endothelial cells and pericytes is thought to result in the elaboration of TGF-beta, an inhibitor of endothelial cell proliferation. However, under certain circumstances, TGF-beta can also promote angiogenesis. Additionally, the extracellular matrix of tumor vessels is different. The basement membrane surrounding the vessels is reduced, there are higher concentrations of hyaluronic acid and lower concentrations of sulfated proteoglycans. The tumor vessels have increased permeability, which may be due in part to the reduced basement membrane, in part to increased fluid pressure in tumors and in part to the elaboration of permeability factors, as well as to modification or reduction of cell adhesion molecules. In addition, the increased permeability of the tumor vasculature may be due to stimulation of nitric oxide release by FGF. All of these features would facilitate entry of tumor cells into the lumen in a manner not possible for normal blood vessels. An alternative source of angiogenic factors is the stroma, which is specific to the breast and contains a variety of cells including fibroblasts, macrophages and adipocytes. The stroma functions as a source and storage site for cytokines and growth factors. The possibility that the stroma is abnormal in tumorogenesis has yet to be investigated. Although recent progress has led to the accumulation of much knowledge on the subject of angiogenesis, that information has yet to be synthesized in a manner that would allow the rational consideration of new treatment modalities. Moreover, that knowledge has been developed from studies of normal tissues, bone marrow, and many different tumors. The purpose of this initiative is to focus on breast tumors and on the specific mechanisms of stimulation and inhibition of angiogenesis in those tissues. The powerful tools of molecular biology and immunology combined with animal models and possibly cell lines provide the means to increase knowledge in this area. Lastly, although the lymphatic system is known to play a critical role in the process of metastasis, it remains unclear whether there are lymphatics within the breast tumor and how the tumor vasculature relates to the host lymphatic system. Research Topics The following suggestions are given only as examples. They are not intended to represent research directions to which the NHLBI would give special emphasis. Investigators are urged to utilize their own knowledge of the subject in preparing a response to this RFA. o changes in tumor cell gene expression that elicit angiogenesis in breast tumors o mechanisms underlying the expression of receptors for angiogenic factors on endothelial cells o interactions between tumor cells, circulating cells, and endothelium in breast tumors o role of the stroma in promotion of angiogenesis o mechanisms that direct endothelial cell migration into the tumor o molecular regulation of angiogenic factor production by breast cells o mechanisms of control of gene expression in endothelial cells residing in breast tumors o relative roles of tumor cells and altered endothelial cells in the modification of extracellular matrix associated with tumor capillaries o role of hormones in the angiogenic process in breast cancer o endogenous inhibitors of angiogenesis o the relative roles of specific oncogenes and tumor suppressor genes in modulating the process of metastasis o the relationship of the tumor vasculature and possible lymphatics to the host blood vessels and lymphatic system Investigators should be aware that NIH requires applicants to comply, where feasible and appropriate, to the inclusion of minorities and women in study populations. SPECIAL REQUIREMENTS Although multidisciplinary approaches are encouraged, it is not the intent of this RFA to solicit applications for large studies that would encompass a variety of independent projects, e.g., program projects. This program will not support clinical trials or large epidemiological studies. In general, funds will not be provided for the purchase and installation of expensive, equipment. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need and promise, and in accordance with PHS policy governing such awards. Upon initiation of the program, the Division of Heart and Vascular Diseases will sponsor periodic meetings to encourage the exchange of information among grantees and to stimulate collaboration. Applicants should include their budget request funds for travel to an annual one-day meeting, most likely to be held in Bethesda, Maryland, and should also include a statement indicating their willingness to participate in these meetings. STUDY POPULATION 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 9, 1994 (FR 59 11146-11151) 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 August 1, 1994, 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 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 subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 557 Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application for PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301-710-0267). The RFA label in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could delay processing of the application such that it may not reach the review committee in time for review. In addition, to identify the application as a response to this RFA, Check "YES", enter the title "Angiogenesis in Breast Cancer", and the RFA number HL-94-014 on Line 2a of the face page of the application. Send or deliver 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 Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to the Chief, Centers and Special Projects Section, at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants; otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Applications must be received by September 13, 1994. If an application is received after that date, it will be returned to the applicant. 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. Schedule Letter of Intent Receipt Date: August 1, 1994 Application Receipt Date: September 13, 1994 Review by NHLBI Advisory Council: February 1995 Anticipated Award Date: May 1995 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by NIH staff for completeness and responsiveness. Incomplete applications will be returned without further consideration. If the application is complete but not responsive to the RFA, NHLBI staff will contact the applicant to determine whether to return the application or to submit it for review in competition with unsolicited applications at the next review cycle. Applications may be triaged by an NHLBI peer review group on the basis of relative competitiveness. The NIH will withdraw from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and institutional official. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NHLBI. The second level of review will be provided by the National Heart, Lung, Blood Advisory Council. Review Criteria The review criteria are: o the novelty, originality, and feasibility of the approach and the adequacy of the experimental design o the competence of the principal investigator and collaborators to accomplish the proposed research, and the commitment and time they will devote to the project o the suitability of the facilities to perform the proposed research, including laboratories, instrumentation, and data management systems o the appropriateness of the requested budget and duration for the proposed research o the adequacy of plans for interaction and communication of information and concepts among investigators involved in collaborative studies AWARD CRITERIA Applications must fulfill all the eligibility criteria in order to be considered for funding. The most important criterion in selecting awardees will be scientific merit, as reflected in the priority score. However, factors such as program balance and available funds may also enter into the selection of meritorious applications. The anticipated date of award is May 1995. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Dr. Constance Weinstein Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 3C06 Bethesda, MD 20892 Telephone: (301) 496-1081 FAX: (301) 480-6282 Inquiries regarding fiscal and administrative may be directed to: Mr. William Darby Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892 Telephone: (301) 594-7458 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance number 93.837, Heart and Vascular Diseases. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grants policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to 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. .
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