CANCER THERAPY-RELATED USE OF GENETICALLY ENGINEERED MICE

Release Date:  January 28, 2002

PA NUMBER:  PAR-02-051

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Cancer Institute (NCI)
 (http://cancer.gov)

Application Receipt Date:  April 19, 2002

This Program Announcement expires on April 20, 2002, unless reissued.

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA

The goal of this program announcement is to encourage the use of genetically 
engineered mouse cancer models for cancer therapy-related goals.  Mouse 
cancer-prone models with heritable genetic alterations are usually derived to 
explore mechanisms that underlie basic cancer or tumor biology.  Through in-
depth phenotyping, these models are often discovered to have molecular genetic 
profiles and histopathology that are similar to the molecular signatures and 
tumor progression of human malignancies.  Because of the similarities, the 
models may be appropriate to identify molecular targets for therapy or to test 
new molecularly targeted agents.  The models may be credentialed with new 
agents through systematic preclinical trials to discover how well the mice 
mimic the clinical course of human cancer in response, or development of 
resistance, to therapy.  Or the model strains may be used to discover the 
genetic determinants of response to therapeutic agents. 

RESEARCH OBJECTIVES

Background

With increasing frequency, there are new genetically engineered mice (GEMs) 
available that develop tumors whose molecular genetic profiles and 
histopathobiology are similar to the molecular signatures and tumor 
progression of human malignancies.  However, the majority of GEMs are 
generated to explore hypotheses of basic cancer or tumor biology and genetics 
or to verify gene function in vivo.  There is mounting evidence that GEMs may 
prove appropriate for identification of molecular targets for therapy or for 
testing new agents directed at such targets or pathways.  However, these uses 
are largely unexplored.  Additionally, few model developers use new agents to 
undertake systematic, preclinical trials to discover how well their models 
parallel the clinical course of human cancer in response, or development of 
resistance, to therapy.  

At the present time, it is not fully evident how informative or predictive 
GEMs are for human cancer therapy-related applications.  Because GEMs are 
immune-competent animals, they may better indicate the role of immune cells 
and secreted factors in response to therapy than do cultured cells or human 
xenografts in immune-compromised host animals.  Additionally, GEMs may be used 
to define the role of particular genes in response to new agents.  

GEMs may also allow testing of single or multiple agents at various stages of 
tumor progression, including at the very early manifestations of malignancy.  
Cell lines from, or xenografts of, human tumors are not representative of pre-
malignant or early lesions whose response to therapy may differ substantially 
from tumors that have accumulated substantial stochastic genetic changes.  For 
example, several anti-angiogenesis agents were tested in an engineered model 
with defined stages of tumor progression.  One agent was effective in 
eliminating the early lesions, but was ineffective at a later stage.  In 
contrast, a second inhibitor had no effect on early lesions but substantial 
inhibition of late-stage tumor growth.  

There are other examples of GEMs that effectively mimic the clinical course of 
response to therapy and development of resistance.  Subsequent analysis of 
non-responding mice or those that eventually became resistant may reveal 
additional genetic lesions or other changes that account for the observed 
differences.  Non-responding mice are useful for derivation and testing of new 
classes of agents to overcome resistance.  Because these cancer models are 
developed on various strains of inbred mice or on mixed genetic backgrounds, 
they may also be valuable to delineate the genetic determinants of response or 
resistance to therapy. 

Summary

This PA is intended to encourage those who develop GEMs for studies of tumor 
biology to delineate how appropriate they are for cancer therapy-related 
research, and to define the practical limitations to use of GEMs for 
preclinical therapy research.  Where it is advisable, the applicants to this 
PA should include collaborators who are expert in, for example, translational 
research, clinical trials, imaging research, and statistical analysis.  
Applicants are also encouraged to consider subcontracts with companies who can 
provide relevant services that are unavailable at their institutions.  
 
The following are examples of topics that are responsive to this PA; however, 
appropriate subjects are not limited to those given below.

1.  Preclinical trials of appropriate agents in relevant GEMs to determine if 
the timing and penetrance of the tumor phenotype limits the value of the model 
for this use. 

2.  Preclinical trials to credential appropriate GEMs for how well they 
reflect the observed clinical course of human cancers.

3.  Appropriate experiments to determine the pharmacodynamics and 
pharmacokinetics of specific agents in GEMs.

4.  Preclinical trials that incorporate use of high-throughput technologies or 
small-animal imaging to monitor delivery of agents or response to therapy.

5.  Preclinical trials to determine efficacy of new single or multiple agents 
at different stages of tumor progression.

6.  Preclinical trials that examine which aspects of trial design are 
appropriate for experiments with GEMs.

7.  Examination of GEMs and their corresponding normal background strains for 
genetic determinants of therapeutic response.

MECHANISM OF SUPPORT

This PA will use the NIH R01 award mechanism.  As an applicant, you will be 
solely responsible for planning, directing, and executing the proposed 
project.  This PA uses just-in-time concepts.  It also uses the modular 
budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to develop 
an application for support.  Individuals from underrepresented racial and 
ethnic groups as well as individuals with disabilities are always encouraged 
to apply for NIH programs

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Cheryl L. Marks, Ph.D.
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 5000
Bethesda, MD  20892-7380
Telephone:  (301) 594-8778
FAX:  (301) 496-8656
Email:  cm74v@nih.gov

o Direct your questions about financial or grants management matters to:

Mr. Ted Williams
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-8785
FAX:  (301) 496-8601
Email:  williate@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email:  GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the receipt date listed on the first page of 
this program announcement.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR:  
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1)  Contact the NCI program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2)  Obtain agreement from the NCI staff that the NCI will accept your 
application for consideration for award; and,
  
3)  Identify, in a cover letter sent with the application, the staff member 
and the Institute/Center who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised version 
of these grant application types. Additional information on this policy is 
available in the NIH Guide for Grants and Contracts, October 19, 2001 at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed before the 
receipt date listed on the first page of this program announcement.  The CSR 
will not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following aspects 
of your application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move a 
field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider 
alternative tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional support?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance No. 93.396, and is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency review.  
Awards are made under authorization of Sections 301 and 405 of the Public 
Health Service Act as amended (42 USC 241 and 284) and administered under NIH 
grants policies described at http://grants.nih.gov/grants/policy/policy.htm 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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