Full Text PA-95-025

APOPTOSIS MODULATORS FOR TREATMENT OF AIDS-RELATED CANCERS

NIH GUIDE, Volume 24, Number 4, February 3, 1995

PA NUMBER:  PA-95-025

P.T. 34

Keywords: 
  AIDS 
  Cancer/Carcinogenesis 
  Biology, Cellular 


National Cancer Institute

Application Receipt Date:  May 1, 1995

PURPOSE

The purpose of this Program Announcement is to encourage
investigators to discover modulators of the apoptotic process with
the intent of developing new therapies for AIDS-related malignancies.

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 Program
Announcement (PA), Apoptosis Modulators for Treatment of AIDS-Related
Cancers, is related to the priority area of human immunodeficiency
virus/AIDS and 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 202-783-3238).

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 and local
governments, and eligible agencies of the Federal government.
Applications may be submitted from one institution or may include
arrangements with several institutions, if appropriate.  Applications
involving minority institutions are encouraged.  Foreign institutions
are not eligible for First Independent Research Support and
Transition (FIRST) (R29) awards.  Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as
Principal Investigators.

MECHANISM OF SUPPORT

Support for this PA will be the investigator-initiated research
project grant (R01), FIRST (R29) award, or the Interactive Research
Project Grants (IRPG) mechanisms.  If an IPRG is proposed, it must
consist of a minimum of two independent applications (see PA-94-086,
NIH Guide for Grants and Contracts, Volume 23, Number 28, July 29,
1994).  An IRPG may consist of a combination of R01s and R29s or R01s
only, but may not consist solely of R29 applications.  An IRPG may
also contain shared interactive resources (Cores), which must serve
at least two of the research projects in order to facilitate
achievement of the Group's common research goals.  Collaborative
arrangements involving more than one institution are especially
encouraged, including participation of the pharmaceutical industry
where appropriate.

FUNDS AVAILABLE

The NCI has set aside approximately $1.0 million total costs in
Fiscal Year 1995 for the first year of funding for support of
applications received in response to this PA.  The level of support
is dependent on the receipt of a sufficient number and diversity of
applications of high scientific merit and the availability of funds.

Because the nature and scope of the research proposed in response to
the PA may vary, the sizes of awards will vary.  It is expected that
four or five awards will be made.

RESEARCH OBJECTIVES

Background

Human immunodeficiency virus (HIV) infection causes a pronounced
decrease in CD4+ T helper cells resulting in loss of immune function.
AIDS patients have an unusually large incidence of highly aggressive
malignancies related to their attenuated immune functions.  New and
more effective methods to treat AIDS associated cancers are badly
needed.  Recent evidence suggests that apoptosis is an important
component of cancer therapy.  The intrinsic killing power of drugs or
radiation may be less important than the ability of these agents to
stimulate tumor cells to kill themselves.  Apoptosis may also be
relevant to some aspects of drug resistance and may explain why tumor
cells are more sensitive to cell killing than are normal cells.
Exploitation of this concept of tumor cell death for the development
of new and more effective therapies provides an exciting and
potentially fruitful challenge.

Objectives and scope

Apoptosis is a topic of considerable research interest.  Numerous
research projects have been undertaken to delineate the mechanisms
and molecular factors that regulate the process.  As a result of
these efforts, an understanding of apoptosis encompassing a broad
range of cellular mechanisms is emerging.  The goal of this PA is the
exploitation of these exciting advances in the understanding of the
mechanism of apoptosis for discovery of modulators of the apoptotic
process with the intent of developing new therapies for AIDS-related
malignancies.

Applications focused on exploitation of current knowledge of
apoptosis for the discovery of agents that modulate the process are
encouraged.  Applications designed solely to understand the basic
principles of apoptosis are not encouraged as part of this
initiative.

Examples of research topics include, but are not limited to:

o  Altering gene expression or activity of gene products which
regulate apoptosis,i.e., p53, c-myc, bcl-2, or bax.

o  DNA repair mechanisms.

o  Stimulation of oxidative damage or stress.

o  Cell signalling mechanisms which influence apoptosis.

o  Development of in vitro and in vivo model systems for discovery of
apoptotic modulators.  Applications could include biological
evaluation of active agents using these models.

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.

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.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be
used.  Forms are available at most institutional offices of sponsored
research or from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 5333 Westbard Avenue,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  Receipt date
for applications for this AIDS-related research PA is May 1, 1995.
The title and number of the PA must be typed in Section 2a of the
face page of the application.

FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

If an IRPG is proposed, each application must be identified along
with the number of the PA and the phrase "Investigator-initiated
IRPG".  All R01 or R29 applications constituting the proposed IRPG
cohort must be submitted in a single package, whether or not the
applications arise from the same institutions.  For detailed
instructions for preparations and submission of IRPG applications,
refer to PA-94-086, NIH Guide for Grants and Contracts, Volume 23,
Number 28, July 29, 1994.

A signed, typewritten original of the application and five legible
copies must be sent or delivered in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit by study sections of the Division
of Research Grants, NIH, in accordance with the standard NIH peer
review procedures.  Following scientific/technical review, the
applications will receive a second-level review by an appropriate
National Advisory Council/Board.

Applications that are complete and responsive to the program
announcement will be evaluated for scientific and technical merit by
an appropriate peer review group convened 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 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

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

AWARD CRITERIA

For Fiscal Year 1995, the NCI has set aside $1 million for this
initiative.  However, applications will compete for funding with all
other approved applications, and funding decisions will be based on
scientific merit as determined by peer review and programmatic
priorities.

INQUIRIES

Inquiries concerning this PA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. George S. Johnson
Division of Cancer Treatment
National Cancer Institute
Executive Plaza, North, Room 832
Bethesda, MD  20892-7450
Telephone:  (301) 496-8783
FAX:  (301) 496-8333
Email:  meadt@dctod.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Marci Bollt
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Suite 243 MSC-7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 242
FAX:  (301) 496-8601
Email:  bolltm@gab.nci.nih.gov

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 HHS policies and grant regulations.  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 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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