COMPETING SUPPLEMENTS FOR ORGANOTYPIC MODELS OF CANCER

RELEASE DATE:  January 29, 2002

PAR NUMBER:  PAR-02-052

EXPIRATION DATE:  This Program Announcement expires on March 29, 2002, 
unless reissued.

PARTICIPATING INSTITUTES AND CENTERS (ICs):

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

Application Receipt Date:  March 28, 2002

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 Special Requirements
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

An important class of mammalian models with considerable potential for cancer 
research is one in which the multiple cell types from a particular tissue are 
studied together, as reconstituted multi-cellular systems, or as tissue 
explants in culture or in animals as transplants.  However, such model systems 
are often insufficiently developed or under-utilized.  The intent of this 
program announcement is to encourage NCI-funded investigators to explore the 
development and use of alternate model systems that more closely resemble 
normal tissue or emerging tumors than do dispersed cells cultured on plastic. 

RESEARCH OBJECTIVES

Background

Mammalian model systems comprised of the multiple cell types from a particular 
tissue may be reconstituted or transplanted in culture or into appropriate 
live animal hosts.  Sufficient advances in tissue engineering and gene 
delivery technologies make it feasible to use multi-cell systems to explore 
some of the questions normally pursued with in vivo models.  Some examples are 
the role of specific cell types and their interactions, effects of alterations 
in particular genes or factors, or interactions between genes and endogenous 
factors in the genesis and progression of cancer from specific cell types.  
This warrants development of alternate systems that more closely resemble 
normal tissue or developing tumors than do dispersed cells cultured on plastic.  

There are a number of possible approaches to the design and use of organotypic 
cultures.  For example, in one published study, a model system of 
spontaneously immortalized human keratinocytes recapitulated the three-
dimensional micro-environment and epithelial-mesenchymal interactions of human 
stratifying epithelium.  Exposure of the model system to 2,3,7,8-
tetrachlorodibenzo-p-dioxin altered normal skin homeostasis exclusively by 
effects on the keratinocyte differentiation program, resulting in profound 
changes in tissue architecture.  

Another recent study used a human papilloma virus (HPV)-infected human 
cervical cancer cell line grown as a "raft" culture.  Only is this culture 
system, which has a tissue architecture that closely resembles the cervix, did 
the cancer cell line duplicate the entire HPV cell cycle, even producing 
infectious viral particles.  Superinfection with adeno-associated virus (AAV) 
reduced HPV replication, and caused significant changes to epithelial 
morphology consistent with the ability of AAV to interfere with development of 
cervical carcinoma.  Another similar raft culture of human keratinocytes was 
used to delineate many of the elements that restrict adenovirus replication to 
cells expressing the E6 and E7 genes of HPV to enable delivery of gene therapy 
exclusively to tumor cells.

Further examples include organotypic cultures of brain slices and human 
duodenal mucosa.  In the former instance, biolistic gene delivery was used to 
define the neuronal cell expression patterns of promoter deletion constructs 
of two specific genes, providing important preliminary results to delineate 
the design of gene constructs for promoter studies in transgenic models.  In 
the latter case, the human duodenal organ cultures were used to verify the 
cell-type source and mechanisms of action of particular cytokines in 
regulation of cell proliferation, apoptosis, and differentiation in human 
small intestinal epithelium.   

Summary

The goal of this PA is to encourage the design and use of organotypic cell 
cultures.  These systems may be used to delineate the roles of the different 
cell types in a tissue or organ, define their interactions, and study the 
contribution of normal or mutated phenotype of each to tumors that arise in 
that organ.  The cells themselves may be normal, tumor-derived, or genetically 
engineered, and used in various combinations.  Organotypic models may provide 
alternatives to cell culture models that are currently used for a variety of 
research applications, for example, to screen molecularly targeted therapy or 
test delivery strategies for new agents.  They may pave the way for derivation 
of additional animal models of epithelial malignancies that alter the types of 
cells found in the tissue stroma.  
 
MECHANISM OF SUPPORT

This PA will use the NIH competing supplement mechanism to ongoing NCI R01, 
P01, or U01 grants.  As an applicant, you will be solely responsible for 
planning, directing, and executing the proposed project.  The total project 
period for an application submitted in response to this PA may not exceed the 
project period of the parent grant.  Direct costs for the supplement may not 
exceed $50,000/year.

This PA uses just-in-time concepts.  It also uses the modular budgeting 
format. (see http://grants.nih.gov/grants/funding/modular/modular.htm).

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.   

SPECIAL REQUIREMENTS

Grants that are eligible for supplementation in response to this program 
announcement are NCI-funded R01, P01, and U01 grants whose project end dates 
are 04/30/04 or later.

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:

Suresh Mohla, Ph.D.
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Suite 5000
Bethesda, MD  20892
Telephone:  (301) 435-1878
FAX:  (301) 480-0864
Email:  sm82e@nih.gov

o Direct your questions about peer review issues to: 

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD  20892-8329
Telephone:  (301) 496-3428
FAX:  (301) 402-0275 
Email:  ncidearefof@mail.nih.gov

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

Ms. Dena Solomon
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7208
FAX:  (301) 496-8601
Email:  ds86p@nih.gov

APPLICATION PROCEDURES  

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 by the receipt date listed at the beginning 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.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and three 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)

At the time of submission, two additional copies of the application must be 
sent to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD  20892-8329
Rockville, MD  20852 (for express/courier service)

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE 
WILL NO LONGER BE ACCEPTED.  This policy does not apply to courier deliveries 
(i.e. FEDEX, UPS, DHL, etc.) 
(http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html).  This 
change in practice is effective immediately.  This policy is similar to and 
consistent with the policy for applications addressed to Centers for Scientific 
Review as published in the NIH Guide Notice 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html.

APPLICATION PROCESSING: Applications must be received by the date listed on 
the first page of this PA.  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

Upon receipt, applications will be reviewed for completeness by the CSR and 
the NCI program staff for adherence to the guidelines of this PA.  
Applications not adhering to the guidelines of this PA, and those applications 
that are incomplete as determined by CSR or by NCI program staff, will be 
returned to the applicant without review.

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

REQUIRED FEDERAL CITATIONS 

Clinical trials supported or performed by NCI require special considerations.  
The method and degree of monitoring should be commensurate with the degree of 
risk involved in participation and the size and complexity of the clinical 
trial.  Monitoring exists on a continuum from monitoring by the principal 
investigator/project manager or NCI program staff or a Data and Safety 
Monitoring Board (DSMB).  These monitoring activities are distinct from the 
requirement for study review and approval by an Institutional review Board 
(IRB).  For details about the Policy for the NCI for Data and Safety 
Monitoring of Clinical trials see:  
http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm.  For Phase I and II 
clinical trials, investigators must submit a general description of the data 
and safety monitoring plan as part of the research application.  See NIH Guide 
Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II 
Trials" for additional information:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.  Information 
concerning essential elements of data safety monitoring plans for clinical 
trials funded by the NCI is available:  
http://www.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines.

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of 
clinical research, updated racial and ethnic categories in compliance with 
the new OMB standards, clarification of language governing NIH-defined Phase 
III clinical trials consistent with the new PHS Form 398, and updated roles 
and responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable, 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned 
without review. 

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.



Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


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