Full Text CA-92-07
 
DOMESTIC ANIMAL MODELS FOR RETROVIRUS-ASSOCIATED HUMAN CANCERS
 
RFA:  CA-92-07
 
P.T. 34

Keywords: 
  Disease Model 
  Etiology 
  Viral Studies (Virology) 
  Cancer/Carcinogenesis 
  Antivirals 

 
National Cancer Institute
 
Letter of Intent Receipt Date:  February 28, 1992
Application Receipt Date:  April 28, 1992
 
PURPOSE
 
Retroviruses isolated from mammalian species have the potential to
provide valuable basic information on the etiology and mechanism(s) of
cancer induction by viruses and to serve as models for evaluating
antiviral agents prior to human clinical trials.  The occurrence of
neoplastic sequelae in retrovirus-infected animals supports the view
that these viruses may be directly or indirectly involved in the
etiology of malignancies.  The identification and development of
suitable animal models of viral neoplasia may aid in investigations of
the mechanisms of cancer initiation and progression, ultimately
providing a better understanding of the role of viruses in the etiology
of human cancer.  The Congress, in both FY 90 and FY 92, has expressed
its interest in retroviral infections in large domestic animals as
excellent models for retroviral-induced diseases in humans such as
leukemia, lymphosarcoma, and AIDS.
 
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), Domestic Animal Models for Retrovirus-
Associated Human Cancers, is related to the priority area of cancer
etiology.  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
 
Non-profit and for-profit, domestic and foreign, organizations and
institutions, governments and their agencies are eligible to apply.
Applications from minority individuals and women are encouraged.
 
MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) individual research grant, R01. Applicants will be
responsible for the planning, direction, and execution of the proposed
project.  In addition to traditional R01 grants, investigators may
submit applications for collaborative efforts using the Interactive
Research Project Grant (IRPG), which was recently announced by the NCI
(PA-92-29) in the NIH Guide for Grants and Contracts (Vol. 21, No. 1,
01/10/92).  Potential applicants interested in the interactive project
approach should consult that program announcement for specific
guidance.  A minimum of three independent investigators with related
research objectives may submit concurrent but independent R01 grant
applications that share a common focus.  Each application that is part
of an IRPG package will be considered on its own merit as an individual
research project.  Therefore, applicants for IRPGs MAY NOT concurrently
submit R01 applications that represent significant duplication of
efforts described in the applicant's IRPG.  In this regard, it should
be noted that the National Cancer Institute (NCI) will consider funding
meritorious individual IRPG applications if it is not possible to fund
the IRPG package as a whole.  Except as otherwise stated in this RFA,
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.
 
This RFA is a one-time solicitation.  Future unsolicited competitive
continuation applications will compete with all other
investigator-initiated applications and be reviewed by the Division of
Research Grants (DRG).  If the NCI determine that there is a sufficient
continuing program need, a request for competitive continuation
applications will be announced.  Only recipients of awards under this
RFA will be eligible to apply.
 
FUNDS AVAILABLE
 
Approximately $1,750,000 in total costs per year for four years will be
committed to fund applications that are submitted in response to this
RFA.  It is anticipated that five to seven awards will be made.  The
level of funding is dependent on the receipt of a sufficient number of
applications of high scientific merit.  The total project period for
applications submitted in response to the present RFA may not exceed
four years.  The earliest feasible start date for the initial awards
will be September 1992.  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
 
Progress in the development of models of viral-associated malignancies
of large domesticated animals has been hampered due to the indolent
nature of the disease course, the limited number of livestock animals
that develop malignancies, and the diversity of viruses that can induce
neoplasia or play a role as an etiologic co-factor.  In order to
address these issues in a systematic and timely way and in response to
earlier Congressional interest in basic research on retroviruses of
large domesticated animals, a workshop entitled "Animal Models of
Retrovirus-Associated Malignancies" was convened by the Biological
Carcinogenesis Branch, Division of Cancer Etiology (DCE), NCI, on
November 15, 1990.  The purpose of the workshop was to assess the
current state of knowledge of retroviral infections in animals, the
etiology of neoplasms in domestic animals, and the areas of research
that might require stimulation or resources for continued progress.
 
The neoplastic potential of various retroviruses and the different
molecular mechanisms by which viruses might be involved in the
neoplastic processes have yet to be fully enumerated.  Retroviruses can
transcriptionally activate host genes by cis- or trans-mechanisms or
inactivate host genes by direct insertional disruption.  In the avian
and rodent system, retroviral insertional activation (and, in one case,
inactivation) of cellular oncogenes represents a key step in
oncogenesis caused by nonacute retroviruses that do not carry their own
oncogenes.  A by-product of this process is the genesis of
oncogene-transducing retroviruses.  Little is known about the ability
of the host to restrict the replication of retroviruses, and thus it is
not known which host factors determine whether a virus replicates
lytically or might be involved in the initiation or progression of
neoplastic sequelae.  Some retroviruses, such as the equine infectious
anemia virus in horses, have not been shown to be involved in malignant
sequelae, while other retroviruses, such as the feline leukemia
viruses, are frequently involved in malignancies.  Studies on the
pathogenesis of cancers of viral origin from animal models should
result in new knowledge relevant to human cancer.
 
This RFA focuses on the retroviruses of domestic livestock because
unique virus models have been identified that display correlative
aspects to human neoplasia.  For example, bovine leukemia virus, the
causative agent of lymphosarcomas in cattle, is closely related to
HTLV-1, the etiologic agent of adult T-cell leukemia in humans; ovine
pulmonary carcinoma is a naturally occurring retrovirus- associated
pulmonary neoplasm of mature sheep; a nasal carcinoma in sheep has
recently been etiologically linked to a type D retrovirus infection;
and the bovine papillomavirus induces esophageal, ocular, and skin
carcinomas in the cow that are related to human papillomavirus-induced
malignancies.
 
Research Goals and Scope
 
Progress in research on retroviruses of domestic livestock models has
been limited by the indolent course of the disease and the fact that
the neoplasms may occur in a limited percentage of animals.  Other
limitations include the difficulty in propagating the viruses in tissue
culture systems, a lack of reagents for typing of cells of the animal's
immune system, nucleic acid probes for some viruses are either not
available or are not well characterized, and monoclonal antibodies for
some viral antigens and host cell proteins with which the viruses
interact are not available.  Additionally, only a small number of
scientists are actively conducting research on each virus.  One goal of
this RFA is to encourage collaborations between scientists with
complementary areas of research expertise, such as molecular biology of
retroviruses and pathogenesis or immunology, with the intent of
accelerating progress in these important cancer models.  The overall
purpose of the RFA is to help stimulate research activity in these
retrovirus cancer models and overcome these limitations.
 
The objectives of the RFA are to encourage basic research on retroviral
pathogenesis in domestic livestock animals.  These studies will aid in
the understanding of the properties of viruses and features of the host
and its response that determine disease progression from initial virus
infection to neoplastic sequelae.  For the purposes of this RFA,
domestic animals include cows, horses, sheep, goats, and pigs;
specifically excluded are retroviruses of dogs, cats, primates and
avian species.  Collaborative efforts between scientists with
complementary areas of research expertise will be encouraged.  The
areas of proposed investigation include:  (1) investigations of the
oncogenic mechanisms in domestic livestock retroviruses; (2)
investigation of cancer etiology and viral pathogenesis from initial
infection through the development of pre-neoplastic lesions and
neoplastic sequelae with retroviruses of domestic livestock; (3) the
role of RNA and DNA viral co-factors in cancer etiology animal models
and definition of virus- and co-factor-host interactions and immune
function alterations in the host that dispose the host to neoplastic
processes; (4) investigations to assess the role of the host immune
system and host genetic factors in the control and limitation of virus
replication, and the susceptibility or resistance of animals to
oncogenic processes; and (5) studies on the expression and regulation
of viral and/or associated host cell genes in pre-neoplastic lesions
and malignant tissues from retrovirus-infected domestic livestock
animals.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by February 28, 1992, 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 is being
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 also 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. Kenneth J. Cremer
Program Director, AIDS Virus Studies
Biological Carcinogenesis Branch
Division of Cancer Etiology
National Cancer Institute
Executive Plaza North, Room 540
Bethesda, MD  20892
Telephone:  (301) 496-6085
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 10/88, reprinted
9/89) must be used in applying for these grants.  These forms are
available at most institutional business offices; from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda, MD
20892, telephone 301/496-7441; and from the NCI Program Director named
above.
 
The RFA label available in the 10/88-9/89 revision of the PHS 398
application form must be affixed to the bottom of the face page.
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 2
of the face page of the application form, "Response to Specific Program
Announcement" and the YES box must be marked.
 
Submit a signed, typewritten original of the application, including the
Checklist, and four signed, exact photocopies, in one package to the
address below.  The photocopies must be clear and single sided.
 
DIVISION OF RESEARCH GRANTS
National Institutes of Health
Westwood Building, Room 240
5333 Westbard Avenue
Bethesda, MD  20892
 
At time of submission, send two additional copies of the application
to:
 
REFERRAL OFFICER
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892
 
If the applicant has an approved assurance covering the research
(multiple project assurance for animal subjects), the applicant must
provide, with the application, verification of the institutional animal
care and use committee (IACUC) approval if animals are involved.  These
reviews and approvals must occur PRIOR TO SUBMISSION of the
applications for award and the certifications and verifications must be
SUBMITTED WITH the applications.  Failure to provide required
certifications and verifications within applications could result in
deferral or rejection.  If animals will be subjects of the research at
PERFORMANCE SITES OTHER THAN THE APPLICANT ORGANIZATION, the applicants
must identify, within the application, the assurance status of each
participant.  Failure to provide this information within applications
could result in deferral or rejection.
 
Applications must be received by April 28, 1992.  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 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 NIH 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 responsive 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 in the
INQUIRIES section.
 
In cases where 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 clearly are
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.
 
o  The scientific merit, technical and medical significance of the
proposed research, including the adequacy and quality of the
methodological approach and the research design.  Familiarity with the
proposed techniques must be demonstrated, e.g., by the presentation of
preliminary data.
 
o  The expertise and qualifications of the Principal Investigator and
proposed staff and/or collaborators to perform the proposed
experiments.
 
o  Documentation of the adequacy of the facilities and resources.
 
o  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 Institute and the priorities of the
National Cancer Program.
 
AWARD CRITERIA
 
The anticipated date of award is September 1992.
 
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 and may be directed to Dr. Kenneth
Cremer at the above address.  The Program Director welcomes the
opportunity to clarify any issues or questions from potential
applicants.
 
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 grant 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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