Full Text CA-93-036

VIRAL INTERACTIONS WITH p53 IN HUMAN CANCER

NIH GUIDE, Volume 22, Number 27, July 30, 1993

RFA:  CA-93-036

P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Viral Studies (Virology) 
  Biology, Molecular 


National Cancer Institute

Letter of Intent Receipt Date:  September 15, 1993
Application Receipt Date:  November 23, 1993

PURPOSE

The National Cancer Institute (NCI) invites investigator-initiated
research grant applications for support of basic studies on the
molecular mechanisms by which DNA tumor viruses (such as
papillomavirus, SV40, adenovirus) interact with p53, thereby providing
new insight into viral oncology and human tumorigenesis.

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 Request
for Applications (RFA), Viral Interactions with p53 in Human Cancer, is
related to the priority areas of cancer and women's health. Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0) or "Healthy People 2000" (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.  Foreign
institutions and organizations are not eligible for the First
Independent Research Support and Transition (FIRST) Awards (R29).
Applications from minority and women investigators are encouraged.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) research project grant (R01) and the FIRST Award (R29).
Applicants will be responsible for the planning, direction, and
execution of the proposed project.  The total project period for
applications submitted in response to this RFA may not exceed five
years.  Awards will be administered under PHS grants policy as stated
in the Public Health Service Grants Policy Statement, DHHS Publication
No. (OASH) 90-50,000, revised October 1, 1990, and 45 CFR Part 74 and
Part 92, as applicable.

The anticipated award date is July 1, 1994.  Because the nature and
scope of the research proposed in response to this RFA may vary, it is
anticipated that the size of an award will vary also.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all other
investigator-initiated research grant applications and be peer reviewed
by a chartered study section in the Division of Research Grants (DRG),
NIH.  If the NCI determine that there is a sufficient continuing
program need, a request for competing continuation applications will be
announced.  Only recipients of awards under this RFA will be eligible
to apply.

FUNDS AVAILABLE

Approximately $1,000,000 in total costs per year for up to five years
will be committed to fund applications that are submitted in response
to this RFA. It is anticipated that five to six awards will be made.
The level of funding is dependent on the receipt of a sufficient number
of applications of high scientific merit.  Although this program is
provided for in the financial plans of the NCI, the award of grants
pursuant to this RFA is also contingent upon the availability of funds
for this purpose.

RESEARCH OBJECTIVES

Background

Cancer is a multi-step process that is usually preceded by the
accumulation of mutations in an assortment of genes.  Until recently,
the tumorigenic mutations that have been studied in detail are those
that activate oncogenes.  The discovery of anti-oncogenes or tumor
suppressor genes, by which inactivating mutations elicit tumorigenesis,
has added a new dimension to the understanding of neoplasia.  The
retinoblastoma susceptibility gene (RB) is the prototype tumor
suppressor gene and has been shown to suppress the transformed
phenotype for several different cancers.  The p53 gene is a growth
control gene that plays a key role in the suppression of abnormal cell
proliferation and tumor development.  Mutations in the p53 gene are
becoming the most common genetic alterations in many human cancers.
Genetic abnormalities of p53, some of which may be due to viral
involvement, are functionally implicated in the development of a wide
variety of human cancers, including breast, cervix, bone, colon, liver
and lung.  Many of the viral oncoproteins from DNA tumor viruses such
as human papillomaviruses, simian virus 40 (SV40) and adenoviruses,
which transform cells in culture and induce tumors in animals, act in
part through the functional inactivation of p53 tumor suppressor gene
products resulting in uncontrolled cell growth.

On December 18, 1992, the Biological Carcinogenesis Branch, Division of
Cancer Etiology (DCE), NCI sponsored a workshop entitled "Viral
Interactions with p53 in Human Cancer."  The purpose of this workshop
was to assess the current state of knowledge on the role of viral
protein interactions with p53 in human cancer and to determine whether
or not there are particular research areas that need stimulation in the
form of grants.  This RFA is issued in accordance with the workshop
recommendation that extramural research be stimulated in this area with
set-aside funds.

Research Goals and Scope

The overall goal of this RFA is to stimulate research on the molecular
mechanisms by which viral oncogenes from DNA tumor viruses and p53
interact, thereby providing new insight into human tumorigenesis.
Examples of studies that may be supported under this RFA include, but
are not limited to:  (1) determination of the role of inactivation of
p53 and other tumor suppressor genes in human papillomavirus-induced
cervical cancer; (2) identification and characterization of viral
mechanisms for overcoming apoptosis via p53; (3) determination of the
host immune response to altered p53 and how DNA tumor viral proteins
affect immune recognition of p53; (4) determination of the possible
viral involvement in p53 mutations associated with human breast cancer;
(5) identification and characterization of other viral or cellular
proteins that physically complex with p53 and whose expression may be
modulated by p53; (6) utilization of DNA viruses as probes to study the
interacting pathways that are involved in regulating cell growth; and
(7) study the function of p53 in inducing growth arrest in response to
DNA damage.

SPECIAL REQUIREMENTS

The Principal Investigator is expected to spend a minimum of 20 percent
time and effort on this project.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender, and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 in Sections 1-4
of the Research Plan AND summarized in Section 5, Human Subjects.
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations (i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks,
Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by September 15, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator, the names
of other key personnel, the 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, it is requested
in order to provide an indication of the number and scope of
applications to be reviewed.  It allows NCI 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 Dr. May Wong at the address
listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form 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; from the Office of Grants
Information, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/597-7248; and from the NCI Program Director named below.

The RFA label available in the PHS 398 (rev.9/91) application form must
be affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the application
such that it may not reach the review committee in time for review.  In
addition, the RFA number and title must be typed on line 2a of the face
page of the application form and the YES box must be marked.
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete and
will be returned without review.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, exact, clear and single-sided photocopies,
in one package to:

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

At time of submission, send two additional copies of the application
to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
Executive Plaza North, Room 636
6130 Executive Boulevard
Bethesda, MD  20892

Applications must be received by November 23, 1993.  Applications
received after that date will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by DRG staff for
completeness. Incomplete applications will be returned to the applicant
without further consideration.  Evaluation for responsiveness to the
RFA is an NCI program staff function.  Applications will be judged to
determine responsiveness to the goals and objectives of the RFA.
Applications judged non-responsive will be returned to the applicant
but may be submitted as investigator-initiated research grants at the
next receipt date.  Questions concerning the relevance of proposed
research to the RFA may be directed to program staff listed under
INQUIRIES.

If the number of applications is large compared to the number of awards
to be made, the NCI may conduct a preliminary scientific peer review to
eliminate those applications that are clearly not competitive.  The NCI
will withdraw from further competition those applications judged to be
noncompetitive and notify the applicant and institutional business
official.

Those applications judged to be both competitive and responsive will be
further evaluated according to the review criteria stated below for
scientific and technical merit by an appropriate peer review group
convened by the Division of Extramural Activities, NCI.

1.  Extent to which the proposed research addresses the goals of the
RFA.

2.  The scientific merit, technical and medical significance of the
proposed research, including the appropriateness and adequacy of the
experimental approach and methodology proposed to carry out the
research.  Familiarity with the proposed techniques should be
demonstrated, e.g., by the presentation of preliminary data.

3.  The research experience, expertise, and qualifications of the
Principal Investigator and proposed staff and/or collaborators to
perform the proposed experiments.

4.  Documentation of the adequacy of the facilities and resources
necessary to perform the research.

5.  Appropriateness of the proposed budget and duration in relation to
the proposed research.

The second level of review by the National Cancer Advisory Board
considers the special needs of the NCI and the priorities of the
National Cancer Program.

AWARD CRITERIA

The earliest anticipated date of award is July 1994.

Factors, including the scientific and technical merit reflected in the
priority score, availability of funds, and relevance to selected areas
of programmatic emphasis, will be used to make award decisions.

INQUIRIES

Written and telephone inquiries concerning the objectives and scope of
this RFA and inquiries about whether or not specific proposed research
would be responsive are encouraged.  The Program Director welcomes the
opportunity to clarify any issues or questions from potential
applicants.

Direct inquiries regarding programmatic issues and address the letter
of intent to:

May Wong, Ph.D.
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892
Telephone:  (301) 496-1953

Direct inquiries regarding fiscal matters to:

Mr. Joseph H. FitzGerald
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 15

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
Number 93.393, Cancer Cause and Prevention Research.  Awards are made
under the authorization of the Public Health Service (PHS) Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
U.S.C. 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

.

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