Full Text PA-97-057
 
EPIDEMIOLOGY OF AIDS/RETROVIRAL-ASSOCIATED CANCERS
 
NIH GUIDE, Volume 26, Number 13, April 25, 1997
 
PA NUMBER: PA-97-057
 
P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  AIDS 
  0760082 

 
National Cancer Institute
 
PURPOSE
 
The Division of Cancer Epidemiology and Genetics of the National
Cancer Institute (NCI) invites grant applications for innovative
interdisciplinary studies to better understand the occurrence and
molecular epidemiology of pre-neoplastic conditions and cancers that
occur within the contexts of underlying infection with human
retroviruses such as HIV/AIDS, non-infectious causes of
immunosuppression such as organ transplantation, or subsequent to
anti- retroviral therapies, particularly zidovudine and other
nucleoside reverse transcriptase inhibitors.
 
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 is
related to the priority areas of "Cancer" and "HIV Infection."
Potential applicants may obtain a copy of "Healthy People 2000" (Full
Report: Stock No. 017-001-00474-0 or Stock No. 017-001-10473-1)
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 or Local
Government, and eligible agencies of the Federal Government.  The
total requested project period for an application submitted in
response to this PA may not exceed five years; a foreign application
may not request more than three years support and will receive no
support for indirect costs.  Domestic applications may include
international components but these components will receive no support
for indirect costs. Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal
investigators.
 
MECHANISM OF SUPPORT
 
The mechanism of support will be the individual research project
grant (R01), the First Independent Research Support and Transition
Award (FIRST, R29), the Exploratory Grant (R21), and competitive
supplements to existing NIH-funded research project grants and
cooperative agreements.  Responsibility for the planning, direction,
and execution of the proposed project will be solely that of the
applicant.  In the case of competitive supplements to existing grants
and cooperative agreements, applicants will be required to obtain and
attach to their applications a document indicating that the
submission of their proposal has been approved by the principal
investigator of the research project grant and, if appropriate, the
governing body of the cooperative agreement.  This will be especially
important if the application will require access to biological
specimens from a central repository or to existing databases.  Except
as otherwise stated in this program announcement, awards will be
administered under PHS grants policy as stated in the PHS Grants
Policy Statement, DHHS Publication No. (OASH) 90-50,000 revised April
1, 1994.
 
RESEARCH OBJECTIVES
 
Background
 
The National Cancer Institute has a continuing interest in the study
of the occurrence, natural history,  and molecular epidemiology of
infection- associated pre-neoplastic conditions and cancers occurring
in the context of immunosuppressive conditions such as HIV/AIDS,
other retroviral infections, and organ transplantation.  Some
cancers, notably those associated with oncogenic human viruses, of
the lymphoreticular system (non-Hodgkin's lymphoma and, to a lesser
extent, Hodgkin's disease), soft tissue (Kaposi's sarcoma), and
epithelial tissues (papillomavirus-associated pre-neoplastic
conditions and possibly cancers) are significantly increased in
incidence and display an aggressive pattern of development and
progression in immunosuppressed individuals.  There are reports of
higher than expected numbers of other cancers, such as testicular
seminomas, non-melanomatous skin cancers, hepatocellular carcinomas,
and possibly bladder cancers, developing subsequent to
immunosuppression.  Further, some infection- associated tumors, while
not necessarily occurring more frequently in the presence of
underlying immunosuppression, may occur in unusual forms or be more
refractory to standard therapies.  In addition, it is possible that
some antiretroviral therapies may place individuals at future
malignancy risk, either in terms of frank cancer occurrence or of
clastogenic and mutagenic changes that might predispose to subsequent
tumor initiation or promotion.
 
Infection by human retroviruses, particularly HIV-1/2, is a major
public health problem throughout the world, but particularly in the
developing world. Retroviruses may be directly oncogenic, or may
foster the development of human cancers indirectly through immune
suppression and subsequent reactivation of previously latent human
oncogenic infectious agents. In terms of the contribution of
oncogenic infectious agents to the public health burden of cancer
incidence and mortality, viral-associated cancers tend to occur at
younger ages than non-viral- associated cancers.  The young age at
which most people in the world become infected with HIV/AIDS and
other retroviruses coupled with the time spent living in an
immunodeficient condition that fosters reactivation of previously
latent oncogenic viruses portends that retroviral-associated cancers
will impose a greater cost in years of life lost than other cancers.
While generally the burden is greater in the developing areas of the
world, the increasing length of time that HIV-infected persons can be
maintained by new treatments will result in these cancers  increasing
in the U.S. and Europe as well.
 
The development of incident cancers occurring in renal transplant
recipients was first reported in the 1960's, followed by a few
studies nested within ongoing cohort studies in the 1970's.  It was
thought that the observed increases might be explained by detection
bias occurring as a result of heightened scrutiny of transplant
recipients.  However, as transplantation has become more common, and
survival post-transplant has lengthened, it has been possible to
determine that increased likelihood of detection does not explain all
of the increases.  Research on AIDS-lymphomas was fostered by data on
transplant- associated lymphomas which showed that such lymphomas
were characterized not only by increasing risk, but also by a short
induction period, rapid progression, and brain tropism.  Similar
parallels have been observed with Kaposi's sarcoma and its associated
herpes virus.  Other transplant-associated cancer data, while not
quite as predictive of the AIDS experience as lymphoma, still has had
applications, especially findings on anogenital tumors and skin
cancers.
 
A common theme in transplant-associated malignancies is the role of
coinfections by recognized tumor viruses, just as is being
demonstrated for retroviral-associated malignancies.  Less well-
understood are the mechanisms important to the development of skin
tumors and solid tumors such as colon, lung, and bladder tumors.
Although the immunosurveillance theory has been applied generally in
the case of transplant-associated carcinogenesis, neither is it clear
why not all tumors are increased, nor which components of the immune
system might be contributing to host defense efforts.  Also not clear
is how the transplant situation might be used to forecast trends in
AIDS-associated malignancies as longevity is enhanced, HIV viral load
is decreased, and morbidity abates somewhat over time.
 
Research Scope and Goals
 
The program announcement seeks to encourage research on the
incidence, etiology, and molecular epidemiology of
infection-associated pre-neoplastic conditions and malignancies
occurring in the context of host immunosuppression in the United
States, comparative epidemiologic studies of these malignancies in
several geographic areas, or such studies in areas outside of North
America or Europe. A multidisciplinary approach that links the
expertise of basic scientists with that of epidemiologic and clinical
researchers is encouraged.  Investigations may be conducted in adults
and/or children.  The areas of research listed below are not intended
to be all-inclusive, but are designed to give the applicant some
direction as to the types of research that the NCI is interested in
stimulating.
 
1.  Active surveillance of the prevalence, incidence, molecular
epidemiology, and temporal trends of all cancers and pre-neoplastic
changes occurring in persons already infected with or at high risk
for infection by HIV/AIDS or other human retroviruses, or
immunosuppressed from other conditions such as organ transplantation.
 
2.  Studies conducted through population-based registries or programs
to enhance and utilize tumor registries in areas with high prevalence
of human retroviral infections, or in conjunction with existing
cohorts of persons infected with, or at high risk of acquiring, human
retroviral infections such as HIV/AIDS.
 
3.  The (treated) natural history of cancers and pre-neoplastic
changes in situations where the temporality of observed events,
including timing of first infection or reactivation of existing
infections,  may be addressed.
 
4.  The seroepidemiology and modes of transmission of human oncogenic
agents, particularly human herpes virus 8/Kaposi sarcoma-associated
herpes virus, and the relationship of new infection or reactivation
of latent infection to subsequent development of cancers or
pre-neoplastic conditions in the context of host immunosuppression
from co-infection by HIV/AIDS or other human retroviruses, or organ
transplantation.
 
5.  The association of anti-HIV chemotherapeutic agents on the
occurrence and natural history of ensuing cancers and pre-neoplastic
changes.
 
6.  The role of co-infection by infectious agents, including, but not
limited to, human polyoma/papilloma viruses, human herpes viruses,
hepatitis viruses, and Helicobacter pylori in the etiology and
molecular epidemiology of cancers and pre-neoplastic changes
associated with host immune suppression from conditions such as
HIV/AIDS, infection with other human retroviruses, and organ
transplantation.
 
7.  The effects of host genetics, hormonal changes, environmental
conditions, and human behaviors on the clinical and molecular
epidemiology of infection- associated pre-neoplastic conditions and
cancers occurring within the context of immunosuppressive conditions,
such as those resulting from HIV/AIDS, other retroviral infections,
and organ transplantation.
 
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 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 contain some new provisions that are
substantially different from the 1990 policies.
 
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 9, 1994 (FR 59 11146-11151) 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 under INQUIRIES.  Program
staff may also provide additional relevant information concerning the
policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines for investigator-initiated applications: February 1, June
1, and October 1.  Applications specific to HIV/AIDS may be submitted
for expedited review instead on: January 1, May 1, and September 1.
 
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Information, Office of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301-710-0267, email:
[email protected].  The title and number of the announcement
must be typed in Item 2a on the face page of the application and the
"YES" box 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.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for courier/overnight service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete 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.
 
As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competititve or non-competititve based on their scientific
merit relative to other applications received in response to the PA.
Applications judged to be competitive will be discussed and assigned
a priority score.  Applications determined to be non-competitive will
be withdrawn from further consideration and the Principal
Investigator and the official signing for the applicant organization
will be notified.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
the 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 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.
 
o  conformity to the guidelines of the program announcement.
 
The Initial Review Group will also examine the provisions for the
protection of human subjects and animal welfare and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other approved
applications assigned to the NCI. The following will be considered in
making funding decisions: quality of the proposed project as
determined by peer review, availability of funds, and program
priority.
 
INQUIRIES
 
Inquiries are encouraged, particularly during the planning phase of
the grant applications.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. S.L. Melnick
Division of Cancer Epidemiology and Genetics
National Cancer Institute
6130 Executive Boulevard, Suite 535, MSC 7395
Bethesda, MD 20892-7395
Telephone: 301-496-9600
FAX: 301-402-4279
Email: [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Ms. Theresa Mercogliano
Grants Administration Branch
National Cancer Institute
Executive Plaza South
6120 Executive Boulevard, Suite 243, MSC 7150
Bethesda, MD 20892-7150
Telephone: 301-496-7800, EXT.  243
FAX: 301-496-8601
Email: [email protected]
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.393 and No. 93.856. Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-140, as amended by Public Law 99.158, 42 USC 241 and
285) and administered under DHHS policies and grant regulations 42
CFR 52 and 45 CFR Parts 74 & 92.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.
 
The Public Health Service (PHS) strongly encourages all grant
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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