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 bodyþs 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:
http://www.nih.gov/grants/guide/notice-files/not98-024.html

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:
grantsinfo@nih.gov.  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:
http://www.nih.gov/grants/funding/funding.htm

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:  cf33a@nih.gov

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:  sg42r@nih.gov

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:  pd8n@nih.gov

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:  pg38h@nih.gov

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:  tf12w@nih.gov

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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