Full Text CA-94-020

STUDIES OF THE VIRAL ETIOLOGY OF AIDS-ASSOCIATED MALIGNANCIES

NIH GUIDE, Volume 23, Number 16, April 29, 1994

RFA:  CA-94-020

P.T. 34

Keywords: 
  AIDS 
  Cancer/Carcinogenesis 
  Viral Studies (Virology) 
  Etiology 


National Cancer Institute

Letter of Intent Receipt Date:  June 17, 1994
Application Receipt Date:  July 29, 1994

PURPOSE

The National Cancer Institute (NCI) invites investigator-initiated
research grant applications for support of basic studies on the role
of viruses and other biological agents in the etiology and biology of
malignancies associated with AIDS, including, but not limited to,
Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphomas.

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,
Studies of the Viral Etiology of AIDS-Associated Malignancies, 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).
The total direct cost award for the five-year R29 grant period may
not exceed $350,000 and the direct cost award in any R29 budget
period may not exceed $100,000.  Applicants will be responsible for
the planning, direction, and execution of the proposed project.  The
total project period for each application submitted in response to
this RFA may not exceed five years.

The earliest feasible award date is February 1, 1995.  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 also vary.

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.  However, should 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 upon the receipt of a sufficient
number of applications of high scientific merit.  The earliest
feasible start date for the initial awards will be February 1, 1995.
Although this program is provided for in the financial plans of the
NCI, the award of grants pursuant to this RFA is contingent upon the
availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Patients infected with the human immunodeficiency virus (HIV) are at
high risk for the development of opportunistic infections and
neoplastic sequelae, particularly Kaposi's sarcoma (KS) and
lymphoproliferative diseases such as non-Hodgkin's lymphomas (NHL).
Two NCI-sponsored workshops were held to address problems and
research involving AIDS-associated neoplasms.  A workshop entitled
"The Biology of AIDS Lymphomas" was held on May 11-12, 1992 in which
participants assessed the status of research on AIDS-NHL.  An
"AIDS-Related Malignancies" workshop was held on January 11, 1993 to
stimulate ideas for novel and innovative treatment of AIDS
malignancies.  This RFA is issued in accordance with the workshop
participants' recommendation that extramural research be stimulated
in this area with set-aside funds.

KS was once a rare tumor, but a sudden increase was observed in the
early 1980s in homosexuals newly diagnosed with AIDS.  KS is now
diagnosed at initial presentation in nearly 10 percent of AIDS
patients.  AIDS-KS is characterized by dermal lesions but may
progress and result in visceral involvement in the gastrointestinal
tract, lungs, and liver.  Although the incidence of KS remains fairly
constant during the first seven or eight years following HIV
infection, it increases in the later stages of AIDS with advancing
immune dysfunction and disease progression.  Natural history studies
indicate that KS develops almost exclusively in homosexual men,
suggesting that a sexually transmissible agent(s) may be involved in
the etiology of KS.  KS is characterized by a proliferation of
spindle-like cells, and the lesions are infiltrated by inflammatory
cells, fibroblasts, and endothelial cells.  Cells from KS lesions
produce cytokines and growth factors that promote autologous cell
growth and the recruitment and growth of normal cells.  The HIV tat
regulatory protein functions as a growth factor for cultured AIDS-KS
cells and tat-transgenic mice develop skin lesions similar to human
KS lesions, suggesting tat as a pathogenic link of HIV to KS.
However, the mechanism(s) underlying the pathogenesis of this complex
tumor is not understood.  The etiology of KS has not been established
and the factors and mechanisms involved in the growth of KS cells and
tissues have not been fully investigated.

Lymphomas are a heterogeneous group of neoplasms observed as lymph
node tumors in all population groups of AIDS patients.  Tumor
development is associated with B-cell activation and oligoclonal
proliferation leading to monoclonal or possibly polyclonal expansion
of B-cells.  The majority of AIDS lymphomas are high grade NHLs,
exhibiting aggressive and metastatic growth properties and are
refractory to standard therapies.  An unusually high rate of
extranodal lymphoma occurrence is seen in the central nervous system
(CNS), gastrointestinal tract, bone marrow, heart, skin, lung, oral
cavity and testis.  Approximately 10 to 20 percent of AIDS-NHL are
primary CNS tumors, rare in the normal population.  These properties
suggest that several mechanisms may be responsible for the
development of lymphomas in HIV-infected populations.  Since the
etiology of lymphoid malignancies in the setting of HIV infection is
not known, there are opportunities for expanded research.

The direct role of viruses in the etiology of AIDS-associated
malignancies has been suggested.  HIV undergoes a rapid rate of
mutation in patients, with a number of viral variants existing in an
individual's population of HIV at any time.  Some variants may be
more lymphotropic or have growth advantages when compared to other
variants.  In addition, viral superantigens have been hypothesized to
play a role in B-cell expansion and lymphomagenesis.  The mechanism
by which a viral protein(s) might function as a superantigen(s) and
the relationship to lymphomagenesis are not known, and thus
constitute important areas for additional virologic emphasis.

Virus-host interactions may play a role in oncogenesis.  There has
been an increased incidence of NHLs in relation to reactivation of
Epstein-Barr virus (EBV) or direct antigenic stimulation of lymphoid
cells by EBV. Chromosome translocations and c-myc gene rearrangements
are observed in 75 percent of lymphomas in some groups of
HIV-infected individuals while EBV is detected in only 25 to 40
percent of the lymphomas in other HIV-infected populations,
suggesting that co-factors other than EBV or molecular mechanisms
other than chromosome translocation may be involved in the etiology
of these lymphomas.  AIDS lymphomas may arise through distinct
pathogenic processes including: (1) monoclonal B-cell lymphomas
associated with c-myc gene rearrangement and the presence of EBV
genomes; (2) polyclonal B-cell lymphomas without evidence of EBV
involvement; and (3) monoclonal primary CNS lymphomas associated with
EBV infection but lacking detectable c-myc rearrangement.
Additionally, recently detected rare T-cell NHLs were described in
which the indirect role of HIV was hypothesized.  Cellular proteins
such as c-ras oncogene and p53 may play a role in a multi-stage
progression of lymphoid neoplasia.  The diversity in the possible
etiology of AIDS lymphoid malignancies, in pathology and cell types,
and the molecular characteristics of these neoplasms lead to the
suggestion that lymphomagenesis in the setting of AIDS may be several
distinct disease processes that will require an expanded
multidisciplinary research approach.

Research Goals and Scope

The goal of this RFA is to stimulate research on the role of viruses
and other biological agents in the etiology and biology of
malignancies associated with AIDS, including but not limited to
Kaposi's sarcoma and AIDS-related non-Hodgkin's lymphomas.  Possible
oncogenic or etiologic agents that might interact with HIV include
the Epstein-Barr virus, cytomegalovirus and other human
herpesviruses, human papillomaviruses, human T-lymphotropic viruses
or unknown but suspected retroviruses or other microbes.  Research
might also focus on etiologic agents functioning as a co-factor(s) in
the context of HIV infection or on HIV serving as a co-factor in the
context of other viral or microbial infections.  Proposed areas of
investigation might include but are not limited to:  (1) the role of
viruses and/or biological factors and/or co-factors in the etiology
of AIDS-associated malignancies; (2) interactions between viral
nucleic acid sequences, viral and cellular genes and/or proteins
which might be involved in the initiation and progression of
AIDS-associated malignancies, e.g., interactions with cellular
oncogenes; (3) the role of direct and indirect processes, such as
autocrine and paracrine mechanisms and effects, by which single or
multiple viral or microbial infections play a role in the initiation
and progression of AIDS-associated neoplasms; (4) the use of
currently available, appropriate and well-justified animal models to
investigate the molecular basis of AIDS-associated malignancies; and
(5) investigations of the alteration of pathogenesis and oncogenesis
as a consequence of the immune status of the patient.

SPECIAL REQUIREMENTS

The Principal Investigator of R01 applications must spend a minimum
of 20 percent effort on this project.  FIRST Award Principal
Investigators must devote a minimum of 50 percent effort on this
project.

STUDY POPULATIONS

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 new
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines on the Inclusion of Women and Minorities as
Subjects in Clinical Research," which was reprinted in the Federal
Register of March 28, 1994 (59 FR 14508-14513) to correct typesetting
errors in the earlier publication, and reprinted in the NIH GUIDE FOR
GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by June 17, 1994, a
letter of intent that includes a descriptive title of the proposed
research, the name and address of the Principal Investigator(s), the
names of other key personnel and collaborators, the participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

A letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application.  However, it is
requested in order to provide an indication of the number and scope
of applications to be reviewed, thus allowing 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. Kenneth J. Cremer 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
301/435-0714; and from the NCI Program Director listed under
INQUIRIES.

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.

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, "Response to
Specific Program Announcement," and the YES box must be marked.

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.

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  20852 (If hand delivered or delivery service)
Bethesda MD  20892 (If using U.S. Postal Service)

It is important to send these copies at the same time that the
original and three copies are sent to the DRG; otherwise the NCI
cannot guarantee that the applications will be reviewed in
competition with other applications received by the designated
receipt date.

Applications must be received by July 29, 1994.  An application
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 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.  No addenda or appendix materials
will be accepted after the receipt date unless explicitly requested
by the Scientific Review Administrator.

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 the Program Director 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 non-competitive 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.  The
second level of review by the National Cancer Advisory Board
considers the special needs of the Institute and the priorities of
the National Cancer Program.

The review criteria for the RFA will be:

1.  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 by the presentation of preliminary data.

2.  The demonstrated research experience, expertise and
qualifications of the principal investigator and proposed staff
and/or collaborators to perform the proposed experiments.

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

4.  Where applicable, the appropriateness of an animal or tissue
culture model system chosen for the experiments proposed and the
potential relevance of the model system to AIDS-associated
malignancies.

5.  Where applicable, the demonstration of the availability and
access to appropriate human tissue necessary to perform the proposed
research, the availability of clinical information associated with
human samples, and adequacy of the plans for the inclusion of females
and minorities.

6.  The adequacy of provisions for the protection of human subjects
and the humane treatment of research animals.

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

AWARD CRITERIA

The earliest anticipated date of award is February 1, 1995.

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 opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Kenneth J. Cremer, Ph.D.
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892
Telephone:  (301) 496-6085
FAX:  (301) 496-2025

Inquiries regarding fiscal matters may be directed to:

Mr. Joseph H. FitzGerald
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800, Ext. 215

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 grant
policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74 or
45 CFR Part 92.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.

The Public Health Service 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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