MOLECULAR TARGETS FOR CANCER DRUG DISCOVERY: EXPLORATORY GRANTS

RELEASE DATE:  November 7, 2002

PA NUMBER: PA-03-020

EXPIRATION DATE: February 2, 2003, unless reissued. 

National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)

APPLICATION RECEIPT DATE: February 1, 2003

This Program Announcement (PA) replaces PAR-01-045, which was published in 
the NIH Guide on February 2, 2001.

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism 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 purpose of this Program Announcement (PA) is to promote a full 
utilization of the base of knowledge of cancer biology for cancer-relevant 
target validation and drug discovery for treatment and prevention.  This 
initiative is intended to attract young investigators to embark on career 
choices that include drug discovery, and also experienced investigators to 
apply their expertise to new ventures into cancer therapeutics.  That great 
advances have been made in the past decade in our understanding of the cell 
in health and disease is unquestioned.  Many genes that have mutated and 
molecular processes that have gone awry in a cancer cell have been 
identified.  New information on the difference between a normal and a cancer 
cell continues to be added to this wealth of knowledge.  It is now incumbent 
that this knowledge be used to mount a renewed attack on cancer - for its 
prevention and its treatment.  The challenge is to identify, characterize and 
validate new molecules and molecular processes that can serve as targets for 
drug discovery and initiate a new age of therapeutics.  While the empiric 
approach may have yielded its dividends, the new paradigm demands a more 
reasoned and knowledge-based approach.  For a better appreciation of the 
contextual frame work of this initiative, see the NCI document - The Nation's 
Investment in Cancer Research: Plans and Priorities for Cancer Research - at 
http://plan.cancer.gov

As a companion to this announcement, an additional initiative on Molecular 
Targets for Cancer Drug Discovery under the Small Business Innovation 
Research (SBIR) and Small Business Technology Transfer(STTR) mechanisms is 
also being issued  (See http://grants.nih.gov/grants/guide/pa-files/PA-03-
021.html).  More information can be found on homepages of the Developmental 
Therapeutics Program (http://dtp.nci.nih.gov) and of the Division of Cancer 
Prevention (http://dcp.nci.nih.gov).

RESEARCH OBJECTIVES

Background

The past decade has witnessed an unprecedented accumulation of knowledge of 
the genetic make up and biological function of the cell. In parallel there 
have been technological advancements allowing ever more detailed inquiry into 
its structure and function.  The deciphering of the human genome sequence 
with its boost to functional genomics and proteomics is a harbinger of things 
to come.  A great deal is now known about the molecules and molecular 
processes that sustain the life of the cell.  The structural and functional 
differences between a normal and a cancer cell are being defined with 
increasing precision.  A detailed understanding of such cellular processes as 
signal transduction from within or without, cell cycle regulation, apoptosis, 
migration and metastasis are revealing new points of vulnerability in a 
cancer cell.  The events that occur in the initiation and in the maintenance 
of cancer, including metastasis, are being delineated with increasing 
confidence.  Thus, the stage is set for exciting new approaches in drug 
discovery for cancer prevention and treatment.

Objectives  

The objective of this initiative is to support exploratory studies into 
previously unexplored or under-explored areas of research with the goal of 
drug discovery. The focus will be on new molecular targets and new agents 
that modulate them. The exploration of new targets will include their 
identification and characterization, and establishment of their relevance to 
cancer.  Novel ways of looking at and exploiting previously known targets 
also would be appropriate, but mere extension or reconfirmation of what is 
already known will not be.   These targets may be relevant to any type of 
cancer, including pediatric cancers.  The targets may encompass any cellular 
process, from cell cycle and apoptosis to angiogenesis and metastasis, and 
also the immune system. However, the process must be clearly altered in 
cancer cells and well defined in molecular terms for monitoring and 
manipulation. The development of new assays and innovative technologies for 
monitoring will not be sufficient as stand alone projects but their 
development in conjunction with molecular target identification and 
validation will be appropriate.

The search for molecules or agents that will redirect the behavior of the 
target and subvert its deleterious effect would be a component of this PA. 
These agents could be chemical or biological, man made or naturally 
occurring, but well characterized or subject to characterization as potential 
therapeutic agents.  The particular approach or experimental system to be 
used is left to the imagination and creativity of the investigator, 
consistent with the demands of the specific objective or hypothesis.  Unless 
otherwise justified, the approach should be quantitative and specific, 
whether in vitro or in vivo, and not based on global effects.  Measurement of 
overall cell growth or tumor volume can be acceptable only if they 
demonstrably can be linked to modulation of a specific target(s).  Use of 
modern tools of drug discovery such as rational drug design or high 
throughput screening of combinatorial libraries would be appropriate.  
Preliminary data are not a requirement, but the proposal should reflect clear 
reasoning and demonstrable feasibility.  While the hypothesis-driven nature 
of the proposal may not be overtly evident, it should be reason-driven.

The NCI compound libraries and the Natural Products Repository are available 
to qualified investigators for research purposes.  The information for these 
resources can be found at http://dtp.nci.nih.gov.

MECHANISM OF SUPPORT 

This PA will use the National Institutes of Health (NIH) 
exploratory/developmental (R21) grant award mechanism.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  You may request up to $100,000 direct costs (four budget 
modules) per year unless your application includes consortium costs, in which 
case the limit is $125,000 direct costs (five budget modules) per year.  
These grants are non-renewable and continuation of projects developed under 
this PA will be through the traditional unsolicited investigator initiated 
grant program.

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

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 to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific issues in cancer treatment to:

Suresh K. Arya, Ph.D.
Developmental Therapeutics Program
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, EPN 8153
Bethesda, MD 20892-7456
(For express/courier service: Rockville, MD 20852)
Tel: 301-496-8783
Fax: 301-402-5200
Email: aryas@exchange.nih.gov

Direct your questions about scientific issues in cancer prevention to:

Winfred F. Malone, Ph.D.
Chemoprevention Agents Development Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, EPN 200A
Bethesda, MD 20892-7322
(For express/courier service: Rockville, MD 20852)
Tel: 301-594-0460
Fax: 301-402-0553
Email: malonew@mail.nih.gov

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

Eileen M. Natoli
Grants Administration Branch
National Cancer Institute
6120 Executive Blvd. – EPS 243
Bethesda, MD  20892
Telephone:  (301) 496-8791
Email:  natolie@gab.nci.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001), except that sections a-d of the 
Research Plan may not exceed 15 pages, including tables and figures.  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 on February 1, 2003.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  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 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)

APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE CENTER FOR SCIENTIFIC 
REVIEW 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-02-012.html)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  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.  

Applications that are complete and adhere to the guidelines of this PA will 
be evaluated for scientific and technical merit by an appropriate peer review 
group convened by CSR in accordance with the review criteria stated below.  

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

o  Receive a written critique.
o  Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score.
o Those that receive a priority score will undergo a second level review by  
the National Cancer Advisory 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 

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.  A 
continuing education program in the protection of human participants in 
research in now available online at: http://cme.nci.nih.gov/

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.  Guidance 
for investigators and institutional review boards regarding research involving 
human embryonic stem cells, germ cells, and stem cell-derived test articles 
can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-
044.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. 93.395, Cancer Treatment Research, 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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