NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY

Release Date:  January 10, 2001
 
PA NUMBER:  PA-01-042
 
National Cancer Institute

Letter of Intent Receipt Dates:  June 4, 2001 and February 5, 2002
Application Receipt Dates:       July 12, 2001 and March 13, 2002

THIS PA USES THE “MODULAR GRANT” AND “JUST-IN-TIME” CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

This Program Announcement replaces PAR-99-019, which was published in the NIH 
Guide, November 27, 1998.

PURPOSE
 
This Program Announcement (PA) encourages the use of non-mammalian organisms 
to aid in the discovery of new cancer therapies.  The use of non-mammalian 
organisms for the development of new strategies for prevention, early 
detection, and treatment of cancer is cited in the NCI’s 2002 Bypass Budget ( 
http://plan2002.cancer.gov).  The goal of this PA is the identification of 
key genes and gene products which are altered in human cancer and could be 
exploited as intervention points or targets for the discovery of new cancer 
prevention or treatment drugs.  Projects could focus on validating inferences 
already drawn from comparative study of cancerous and normal cells, exploring 
promising leads from an evaluation of mutations known to be associated with 
cancer development, or testing hypotheses generated by the identification of 
new and unknown gene products, such as those sequenced through the NCI’s 
Cancer Genome Anatomy Project (CGAP) (http://www.ncbi.nlm.nih.gov/ncicgap).  
For example, projects may include development of organisms in which genes in 
key pathways or processes are mutated or organisms in which human transgenes 
are expressed to simulate changes known to occur in human cancers.  These 
genetic manipulations could present a “proof of principle” or validation of 
the importance of the target genes to the development of cancer.  Some 
examples of genes that are well studied in model organisms and known or 
strongly suspected of involvement in cancer include oncogenes, proto-
oncogenes, some cell cycle and signal transduction genes, and DNA repair 
genes.  

The use of multiple grant funding mechanisms allows support for a broad range 
of projects at various stages of development.  The exploratory/developmental 
R21 mechanism supports pilot projects or feasibility studies for new or 
underdeveloped approaches.  Accordingly, a sound rationale and a well designed 
research plan, but not preliminary data, are required. The R01 supports more 
advanced projects and collaborative research efforts between experts in non-
mammalian biology and investigators with experience in mammalian cancer models 
for comparative or proof of principle, validation studies.  

This PA will expire on March 14, 2002, unless reissued.  NIH Grants policies 
apply to these awards.

RESEARCH OBJECTIVES

The goal of cancer therapy is to eliminate malignant cells while sparing 
normal cells.  Current clinically important drugs act as cytotoxic agents by 
binding to or damaging DNA, altering cellular processes, or binding to 
structural proteins such as tubulin causing disruption of cell function.  
Generally, they were discovered as anti-proliferatives without specific 
consideration to site of action.  Thus, as might be expected, they show 
significant toxicity to normal cells which limits their clinical usefulness.  
Targeting specific cell control elements that are altered in tumor cells 
provides a new and potentially valuable approach to identify new, more 
selective, and less toxic agents for the cancer armamentarium.  By focusing on 
a specific target or a target operating in a defined pathway, it should be 
possible to reverse, stop or delay cancer progression.
 
A vast array of altered proteins, regulatory processes, and signaling pathways 
have been implicated in cancer genesis and progression.  However, only a 
select few, such as ras farnesylation and various protein tyrosine kinases, 
have been approached for cancer drug discovery.  Determining which in this 
multitude of  alterations and mutations are sites of vulnerability and are 
thus of importance for intervention, as well as designing approaches to 
exploit these sites for cancer drug discovery, are clearly daunting tasks.  

Non-mammalian organisms offer an extraordinary opportunity to evaluate the 
importance and vulnerability of these sites and to suggest which could be of  
importance for drug discovery.  Key regulatory pathways among eukaryotic 
organisms demonstrate a striking similarity.  Importantly, cancer gene 
homologs and functional pathways containing homologs are of importance in a 
wide variety of cells including those of non-mammalian origin.  Although not 
always of identical importance in humans, common pathways or at least portions 
of such pathways could be considered to be “functional cassettes” performing 
similar tasks within cells or organisms.  For this reason, the use of non-
mammalian organisms, which are easier to manipulate genetically, has been 
valuable in defining new pathways relevant to neoplasia as well as functional 
relationships among the various pathways.  For example, at least 100 genes 
have been identified in yeast which have been classified as “damage control 
elements” whose gene products are involved in functions such as DNA repair, 
cell cycle regulation, and spindle formation.  Several have been shown to have 
homologs in human cells such as the MSH2 and MLH1 repair genes and the ATM 
(ataxia-telangiectasia) cancer susceptibility gene.  Likewise, C. elegans 
biology has defined several genes important to apoptotic pathways with clear 
homologs in humans.  Drosophila have recently highlighted the importance of 
the sonic-hedgehog pathway, whose members include a gene inactivated in basal 
cell carcinoma.  Xenopus and zebrafish are additional non-mammalian organisms 
whose biology is being actively studied and are known to contain homologs of 
cancer relevant proteins.  Importantly, genomic sequences of non-mammalian 
organisms are known as in the case of yeast or are being determined at a rapid 
pace, thus providing a valuable asset for delineating the complexities of 
signaling pathways and control functions.

Applications without a strong rationale for cancer relevance would not be 
responsive to this PA.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health 
(NIH) research project grant (R01) mechanism and the exploratory/developmental 
grant (R21) mechanisms.  Applicants will be responsible for the planning, 
direction, and execution of the proposed project.  All PHS and NIH grants 
policies will apply to applications received and awards made in response to 
this PA.  Applicants for the R21 grant mechanism may request up to $100,000 
direct costs (four budget modules) per year unless the application includes 
consortium costs, in which case the limit is $125,000 direct costs (five 
budget modules) per year.  Support may not exceed two years.  Though the size 
of award may vary with the scope of research proposed, it is expected that R21 
applications will stay within the budgetary guidelines for an 
exploratory/developmental project.  The R21 grants are non-renewable, and 
competitive continuation of projects developed under this program will be 
through the R01 research grant mechanism.  Applications for the R01 grant 
mechanism may not exceed five years.  

Collaborative arrangements involving more than one institution are encouraged, 
including participation of the pharmaceutical industry where appropriate.  

Specific application instructions have been modified to reflect “MODULAR 
GRANT’ and “JUST- IN-TIME” streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by foreign and domestic, for-profit and 
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 
Investigators. 

INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
George S. Johnson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 8153
6130 Executive Boulevard
Bethesda, MD  20892-7456
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email: johnsong@exchange.nih.gov

Direct inquiries regarding fiscal matters to:
 
Jane Paull
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard
Bethesda, MD  20892
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 846-1013
FAX: (301) 846-5720
Email:  paullj@gab.nci.nih.gov

Direct inquiries regarding review issues to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD   20892-8329
Rockville, MD  20852 (for express/courier service)
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: tf12w@nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit, by the dates listed on the first 
page of this PA, a letter of intent that includes a descriptive title of the 
proposed research, the name, address, and telephone numbers of the Principal 
Investigator, the identities of other key personnel and participating 
institutions, and the number and title of the PA in response to which the 
application may be submitted.  Although a letter of intent is not required, is 
not binding, and does not enter into the review of a subsequent application, 
the information that it contains allows NCI staff to estimate the potential 
review workload and plan the review.

The letter of intent is to be sent to the program staff listed under INQUIRIES 
by the letter of intent receipt date listed in the heading of this PA. 

APPLICATION PROCEDURES

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers, and Institute 
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.  Application 
kits are available at most institutional offices of sponsored research and may 
be obtained from the Division of Extramural Outreach and Information 
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, 
Bethesda, MD 20892-7910, telephone 301/435-0714, e-mail: grantsinfo@nih.gov. 
The title and number of this PA must be typed in line 2 on the face page of 
the application form and the YES box must be marked.  For applicants with 
internet access, the 398 kit may be found at: 
http://grants.nih.gov/grants/forms.htm. 

Applicants are strongly encouraged to call Dr. George S. Johnson, as listed in 
INQUIRIES, with any questions regarding adherence to the guidelines of their 
proposed project to the goals of this PA.

SPECIFIC INSTRUCTION FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $250,000 per year for R01 and, up to a total 
direct cost request of $100,000 per year ($125,000 if there are 
consortium/contractual Cost) for R21. (Applications that request more than 
$250,000 direct costs for an R01 in any year must follow the traditional PHS 
398 application instructions.)  The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities 
and Administrative (F&A) costs] for the initial budget period.  Items 8a and 
8b should be completed indicating the Direct and Total Costs for the entire 
proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 
of the PHS 398.  It is not required and will not be accepted with the 
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION -  Prepare a Modular Grant Budget Narrative 
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages). At the top of the page, enter the total direct costs requested for 
each year.  This is not a form page.

o  Under personnel, list all project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

o  For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of all personnel, 
and the role on the project. Indicate whether the collaborating institution is 
domestic or foreign.  The total cost for a consortium/contractual arrangement 
is included in the overall requested modular direct cost amount. Include the 
Letter of Intent to establish a consortium.

o  Provide an additional narrative budget justification if there is a change 
in the number of modules requested from year to year.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three pages 
may be used for each person.  A sample biographical sketch may be viewed at:  
http://grants.nih.gov/grants/funding/modular/modular.htm.

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST -  This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

The applicant should provide the name and phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

Applications not conforming to these guidelines will be considered 
unresponsive to this PA and will be returned without further review.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided 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)

To ensure that the application is received in sufficient time for the review, 
send two additional copies to:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6116 Executive Boulevard, Room 8109, MSC 8329
Bethesda, MD 20892-8329
Rockville, MD 20852 (for overnight/courier service)
Telephone:    (301) 496-3428
FAX:    (301) 402-0275
Email:  tf12w@nih.gov

Applications must be received by the receipt dates listed at the top of 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.

REVIEW CONSIDERATIONS
 
Applications will be reviewed for completeness by the Center for Scientific 
Review and for adherence to the guidelines to this PA by the National Cancer 
Institute.  Incomplete applications will be returned to the applicant without 
further consideration.  Applications that are complete and adhere to the 
guidelines of this PA will be evaluated for scientific and technical merit by 
a special emphasis panel convened by the Division of Extramural Activities of 
the National Cancer Institute in accordance with the standard NIH peer review 
procedures.  As part of the initial merit review, all applications will 
receive a written critique, and may 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 National Cancer Advisory 
Board.

Review Criteria:

The five criteria to be used in the evaluation of grant applications are 
listed below.
 
The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
Within this framework the purpose of this PA is the identification of new 
approaches for cancer discovery through exploitation of unique features of 
non-mammalian organisms. Meritorious projects would include those which 
identify a novel regulatory process in the non-mammalian organism which has 
high relevance to human cancer.

The reviewers will comment on the following aspects of the application in 
their written critiques in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered by the reviewers in 
assigning the overall score, weighting them as appropriate for each 
application.  Note that the application does not need to be strong in all 
categories to be judged likely to have a major scientific impact and thus 
deserve a high priority score.  For example, an investigator 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 this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
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?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches or method?  
Are the aims original and innovative? Does the project challenge existing 
paradigms or develop new methodologies or technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?
 
5.  Environment.  Does the scientific environment in which the 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?
 
The initial review group will also examine: the appropriateness of proposed 
project budget and duration; the adequacy of plans to include both genders and 
minorities and their subgroups and children as appropriate for the scientific 
goals of the research and plans for the recruitment and retention of subjects; 
the provisions for the protection of human and animal subjects; the safety of 
the research environment; and conformance with the NIH Guidelines for the 
Inclusion of Women and Minorities as subjects in Clinical Research.

AWARD CRITERIA
 
Applications will compete for available funds with all other approved 
applications. 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.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), 
a complete copy of the updated Guidelines is available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm.  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are clear and compelling scientific and ethical reasons not 
to include them. This policy applies to all initial (Type 1) applications 
submitted for receipt dates after October 1, 1998.

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 was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

Investigators also may obtain copies of  the policy from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS

Effective October 1, 2000, the NIH requires education on the protection of 
human research participants for all investigators submitting NIH application 
for grants or proposals for contracts or receiving new or non-competing awards 
for research involving human subjects.

All investigators proposing research involving human subjects should read the 
above-referenced policy that was published in the NIH Guide for Grants an 
Contracts, June 5, 2000 (Revised August 25, 2000), and is available at the 
following URL address 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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.  Reviewers are cautioned 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, “Non-mammalian Organisms as 
Models for Anticancer Drug Discovery”, is related to the priority area of 
cancer.  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. 
93.395, Cancer Treatment Research.  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 and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The 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.


Return to Volume Index

Return to NIH Guide Main Index


Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy


Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.