Subject: NIH GUIDE - RFA CA-92-03 - V20(44) 11/22/91
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 21 Nov 91 13:43 EST

Hi Pual,
   Please post this one to the NIH Listserver as:
        RFACA-92-03.911122
                          Dottie
 ---------------------------- Text of forwarded message -----------------------
$$XID RFA CA9203 CA-92-03 P1O1 *****************************************
 
GENE REGULATION OF RADIATION RESISTANCE
 
RFA: CA-92-03
 
P.T. 34; K.W. 0765015, 1002058, 0745062
 
National Cancer Institute
 
Letter of Intent Receipt Date:  January 3, 1992
 
Application Receipt Date:  March 13, 1992
 
INTRODUCTION
 
The Radiation Research Program (RRP), Division of Cancer Treatment
(DCT) of the National Cancer Institute (NCI) invites grant applications
from interested investigators for tightly focused studies that
investigate the molecular/genetic mechanisms responsible for the
inherent radioresistance of human tumor cells.
 
HEALTY 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 Application (RFA), Gene Regulation of Radiation Resistance, is
related to the priority area of cancer.  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, D.C. 20402-9325 (telephone 202-783-3238).
 
BACKGROUND INFORMATION
 
Radiation therapy and chemotherapy are important treatment modalities
for cancer.  The effectiveness of chemotherapy has been restricted,
however, by the inherent and/or acquired drug resistance of tumor
cells.  Many investigations have been directed toward elucidating the
mechanisms of drug resistance.  Both single and multiple drug
resistance (MDR) have been identified and the mechanism of MDR has been
well characterized.  Regardless of the type of drug resistance,
molecular/genetic alterations of the cell commonly appear to be
involved.  MDR has consistently been associated with the increased
expression of P-gylcoprotein, a plasma membrane protein that functions
as an energy-dependant drug efflux pump that reduces intracellular drug
accumulation, thereby conferring resistance to many different drugs.
The genes responsible for encoding the P-glycoproteins have been
identified and termed mdr genes.  Most of the data regarding the
mechanism of MDR corners from in vitro studies that utilized cells
having extremely high levels of drug resistance, levels unlikely to be
seen clinically.  It is not known if a similar mechanism is responsible
for
clinical drug resistance but in vivo studies have suggested that
expression of the mdr genes is probably involved.
 
Studies directed toward identifying the mechanism(s) responsible for
radiation resistance have been few by comparison to those associated
with drug resistance.  The processes associated with radiation
resistance appear to be more complex than those of drug resistance.
Difficulty in developing radiation resistance clones of the cell types
of interest has compounded the problem of identifying the mechanism(s)
responsible for inherent radiation resistance.  A common feature of the
stress response of cells induced by ionizing radiation is the
introduction or activation of proteins believed to protect the cell
against killing.  It has been suggested that these induced proteins may
play a major role in the repair of potentially lethal radiation damage.
Preliminary studies have attributed the changes in protein levels to
alteration, induction, or inhibition of the genes responsible for the
expression and/or regulation of these proteins.  There may be other
mechanisms responsible for radiation resistance that also need to be
elucidated.
 
RESEARCH GOALS AND SCOPE
 
The purpose of this RFA is to stimulate research directed towards
identifying and characterizing the role that molecular/genetic
processes play in the inherent radioresistance observed in some solid
human tumor cells that often exceeds that of the normal cells.  Studies
must be directed toward investigating the various molecular/genetic
events that occur following radiation-induced damage and determining
how they relate to radiation resistance.  These studies may include,
but not be limited to, various facets of gene induction and expression,
i.e., regional transduction pathways, second messenger pathways,
oncogene products, growth factors, and molecular and/or biochemical
factors.
 
By better understanding the radiation resistance associated with human
tumor cells, it may be possible to modulate those mechanisms identified
as playing significant roles and thereby significantly improve the
clinical effect of radiation therapy.  Additionally, important
molecular and cellular prognostic factors for survival or recurrence of
malignancy in patients treated with radiotherapy may be identified from
the proposed studies.
 
MECHANISM OF SUPPORT
 
Support of this program will be through the National Institutes of
Health (NIH) individual research project grant (R01) funding mechanism.
Applicants will be responsible for the planning, direction, and
execution of the proposed project.  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 complete with all investigator-initiated
applications and be reviewed by the Division of Research Grants (DRG).
If the NCI determines 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.
 
Approximately $1,000,000 in total costs per year for three years will
be commited to specifically fund applications submitted in response to
this RFA.  This funding level is dependant on the receipt of a
sufficient number of applications of high scientific merit.  NCI plans
to make multiple (four to five) awards for project periods up to three
years.  The total project period for applications submitted in response
to the present RFA must not exceed three years.  The earliest feasible
start date for the initial award will be December 1, 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
continuing availability of funds for this purpose.
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
nonprofit, public and private organizations, such as universities,
colleges, hospitals, laboratories, units of State or local governments,
and eligible agencies of the Federal Government.  Although NCI-funded
Cooperative Groups are ineligible to apply, individual institutions or
consortia of the Cooperative Groups may apply through their own
institutions.  Domestic applications may include international
components.  Applications from minority individuals and women are
encouraged.
 
A.  REVIEW PROCEDURES
 
Upon receipt, applications will initially be reviewed by the (DRG) for
completeness. Incomplete applications will be returned to the applicant
without further consideration.  Applications will be evaluated by NCI
Program staff to determine responsiveness to the program requirements
and criteria stated in this RFA.  Applications that are judged
nonresponsive will be returned to the applicant by the NCI, but may be
resubmitted as investigator-initiated research grants at the next
receipt date.  Questions concerning the responsiveness of proposed
research to the RFA may be directed to program staff as described in
the INQUIRES section.
 
If the number of applications submitted 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 responsive and competitive will be
further evaluated, using 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
application in light of the special needs of the Institute and the
priorities of the National Cancer Program.
 
B.  REVIEW CRITERIA
 
Applications must be responsive to the stated purpose and objectives of
the RFA.  Factors that will be evaluated in the process of the
scientific review will include:
 
1. The originality, innovativeness, and merit of the proposed research
from a scientific and technical standpoint.
 
2. Assessment of the knowledge, experience, and competence of the
Principal Investigator, associate staff, and scientific collaborators
applicable to the methodology and technology of the proposed scientific
research.
 
3. Adequacy and availability of the facilities and special resources
needed to accomplish the proposed research.
 
4. Documented knowledge of and compliance with the human subjects,
animal welfare, biohazard, and women and minorities requirements
associated with Government-sponsored research.
 
5. Cost effectiveness of the requested budget.  Budget will be
critically examined.
 
C.  SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS
 
NIH and Alcohol, Drug and Mental Health Administration (ADAMHA) policy
is that applicants for NIH/ADAMHA clinical research grants and
cooperative agreements will be 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 should 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 and minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale should
be provided.
 
The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  In addition, gender and racial/ethnic issues should be
addressed in developing a research design and sample size appropriate
for the scientific objectives of the study.  This information should be
included in the form PHS 398 in Section 2, A-D of the Research Plan AND
summarized in Section 2, E, Human Subjects.
 
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognize 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 includes human
biomedical and behavior 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 and 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 will be 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 grant or
cooperative agreements that do not comply with these policies.
 
METHOD OF APPLYING
 
The United States Public Health Service research grant application form
PHS 398 (revised 10/88, reprinted 9/89) must be used in applying for
these grants.  These forms are available at most institutional business
offices; and from the Office of Grants Inquiries, Division of Research
Grants, National Institutes of health, Room 449, Westwood Building,
5333 Westbard Avenue, Bethesda, MD  20892;  Phone (301) 496-7441.
 
The RFA label available in the 10/88 revision of application form PHS
398 (revised 10/88, reprinted 9/89) 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.
 
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
Bethesda, MD  20892  **
 
Also send two additional copies of the application directly to:
 
Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892
 
The applicant must provide with the application certification of
Institutional Review Board (IRB) approval if humans are involved and
verification of the Institutional Animal Care Use Committee (IACUC)
approval if animals are involved.  These reviews and approvals must
occur PRIOR TO SUBMISSION of the application and the certifications and
verifications must be SUBMITTED WITH the application.  Failure to
provide required certifications and verifications with applications
could result in the application being returned as incomplete.  If
animal or humans 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 with the application could result
in the application being returned as incomplete.
 
Applications must be received by March 13, 1992.  If an application is
received after the indicated date, it will be returned.  If the
application submitted in response to this RFA is substantially similar
to a research grant application already submitted to the NIH for
review, but has not yet been reviewed, the applicant will be asked to
withdraw either the pending application or the new one.  Simultaneous
submission of identical applications will not be allowed, nor will
essentially identical applications be reviewed by different review
committees.  Therefore, an application cannot be submitted in response
to this RFA if it is essentially identical to one that has already been
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.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by January 3, 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 an application may is be
submitted.
 
Although the letter of intent is not required, is not binding, and does
not enter into the review of the subsequent applications, it is
requested in order to provide an indication of the number and scope of
applications to be reviewed.
 
The letter of intent is to be sent to:
 
Thomas A. Strike, Ph.D.
Radiation Research Program
Division of Cancer Treatment
National Cancer Institute
Executive Plaza North, Suite 800
9000 Rockville Pike
Bethesda, MD  20892
Telephone: (301) 496-9360
FAX: (301) 480-5785
 
By direct delivery
(express or overnight)
 
Thomas A. Strike, Ph.D.
Radiation Research Program
Division of Cancer Treatment
National Cancer Institute
6130 Executive Boulevard, Suite 800
Rockville, MD  20852
 
INQUIRES
 
Written and telephone inquiries concerning the objectives and scope of
this RFA and inquires about whether or not specific proposed research
would be responsive are encouraged and may be directed to Dr. Thomas A.
Strike at the above address.  The program director welcomes the
opportunity to clarify any issues or questions from potential
applicants.
 
Written and telephone inquiries of a budgetary, administrative, and/or
policy nature may be addressed to:
 
Ms. Carolyn Mason
Grants Management Specialist
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Suite 243
Rockville, MD  20852
Telephone: (301) 496-7800, Extension 59
Fax #: (301) 496-8601
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic Assistance
No. 93.395, Clinical Treatment Research.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS Grants Policies and Federal Regulations
42 CFR 52 and 45 CFR part 74.  This program not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.