MOLECULAR TARGET DRUG DISCOVERY FOR CANCER: EXPLORATORY GRANTS

Release Date:  February 16, 2000

PA NUMBER:  PAR-00-060
 
National Cancer Institute

Letter of Intent Receipt Date:  June 6, 2000
Application Receipt Date:       July 18, 2000
		
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.

PURPOSE

The National Cancer Institute (NCI) defines new, extraordinary research 
opportunities through stated goals in a "Bypass Budget".  Among the 
priorities of the 2001 Bypass Budget was to identify and use molecular 
targets for the discovery and clinical testing of new anticancer agents based 
on the molecular mechanisms that underlie neoplastic transformations, cancer 
growth and metastasis.  Accordingly, the Developmental Therapeutics Program, 
Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI), 
and the Chemoprevention Agent Development Research Group,  the Division of 
Cancer Prevention, NCI  invite exploratory/developmental grant applications 
(R21) to exploit molecular targets for drug discovery.  New insights into our 
understanding of cancer cell biology provide a new opportunity for a 
fundamental re-ordering of approaches to cancer drug discovery.  Rather than 
depending on in vitro and in vivo screens for antiproliferative activity, 
investigators can now focus on new molecular targets and pathways essential 
for the development and maintenance of the cancer phenotype.  As a result, 
the NCI is reorganizing its drug development programs from early drug 
discovery phases to the conduct of clinical trials in order to bring forward 
new types of agents based on strong rationales.  The plan also involves 
changes in the clinical evaluation of new agents that will include 
appropriate measurements to verify target modulation.

In addition to the present announcement, the NCI announces the following 
three related  initiatives in molecular target drug discovery for cancer 
treatment and prevention utilizing additional funding mechanisms:  
Cooperative Agreement (UO1) applications (see 
http://grants.nih.gov/grants/guide/rfa-files/RFA-CA-00-002.html) which are 
suitable for more mature projects defined by preliminary data;  Small 
Business Innovation Research (SBIR, R43) and Small Business Technology 
Transfer Programs (STTR, R41) 
(see http://grants.nih.gov/grants/guide/pa-files/PAR-00-061.html), which 
are directed to those of the small business community who need assistance in 
launching commercial products; and Competing Supplements for existing NCI 
awardees (http://grants.nih.gov/grants/guide/pa-files/PAR-00-062.html), 
which can extend the goals of active grants to include studies related to 
drug discovery.  See the Home Pages of either the 
Developmental Therapeutics Program (http://dtp.nci.nih.gov)  or the 
Chemoprevention Agent Development Group (http://dcp.nci.nih.gov/cb) for 
further information or contact individuals listed under  INQUIRIES  of this 
PA.  Further information on research opportunities regarding molecular 
targets in drug discovery can be found in the NCI ByPass Budget, The Nation’s 
Investment in Cancer Research: A Budget Proposal for Fiscal Year 2001 at 
http://2001.cancer.gov .
		
The purpose of this Program Announcement (PA) is to reorganize the  front 
end  or gateway to drug discovery.  Investigators are being asked to identify 
a novel molecular target, or to validate the target as a basis for cancer 
drug discovery, or to develop an assay for the target.  Given the fact that 
some investigators may already have considerable preliminary data on a 
signaling pathway, they nevertheless may not have focused on the point of 
greatest vulnerability in the pathway and therefore, perhaps the optimal 
point of drug attack.  This PA would support an investigator to validate a 
target and/or develop an assay based on the target.  Applicants may address 
targets related to the treatment of established cancers, or the prevention of 
molecular changes which may cause cancer.  Investigators may use their own 
creativity in defining their approach.  For example, some may prefer to 1) 
use a genetic, structural biology or molecular biology approach to target 
identification/validation using information from genetic studies or studies 
of pathways, whereas others may prefer to  2) identify the function of a 
cellular target after first finding the target as a result of exploring 
binding patterns of natural products or other ligands to the novel target.  
The PA requires that the proposed target(s) in each application be novel and 
not addressed by drugs already approved for clinical use.

Applications submitted to the NIH will be reviewed by the NCI according to 
the criteria established for this PA as described below under REVIEW 
CONSIDERATIONS.

HEALTHY 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 PA, Molecular 
Target Drug Discovery for Cancer, is related to priority areas of human 
cancer treatment and prevention.  Potential applicants may obtain a copy of 
"Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.
 
ELIGIBILITY REQUIREMENTS 
 
These exploratory/developmental grant applications (R21) may be submitted by 
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.  Applications 
may also be submitted by a foreign institution or an intramural laboratory 
from the National Institutes of Health.  For this PA, NIH investigators may 
submit applications, but they may not request or receive funds from this 
program.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.   
MECHANISM OF SUPPORT 
 
The administrative and funding instrument to be used for these awards is the 
exploratory/developmental grant (R21) .  The R21 mechanism provides limited 
funds for short-term research projects, especially for generating preliminary 
data to establish a new, more comprehensive research study.  The 
exploratory/developmental grant (R21) mechanism was designed to give 
resources to an investigator, who may then accumulative data to assess the 
feasibility of a line of research.  Therefore, this is a preferred mechanism 
for projects that would clearly be premature for a traditional research 
project.  The R21 budget requests submitted to this PA may not exceed 
$100,000 in direct costs in any year, including Facilities 
and Administrative (F&A) costs awarded to a collaborating institution, and 
are limited to a total of two years.  These grants are non-renewable and 
continuation of projects developed under this program must be through other 
grant mechanisms.  Unless otherwise noted, all NIH grants policies apply.  
The earliest anticipated award date is April 1, 2001.  

Although no funds for this PA will be used to support intramural projects, 
NIH intramural applicants must verify that the amount of the resources 
allocated from intramural sources does not exceed $100,000 in direct costs.  
For further budget information pertaining specifically to NIH intramural 
applications, see  APPLICATION PROCEDURES  below regarding  Additional 
Instructions for NIH Intramural Project Applicants .
		
Specific application instructions have been modified to reflect  MODULAR 
GRANT  and  JUST-IN-TIME  streamlining efforts as practiced 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.
									
For this PA, funds must be requested in multiples of  $25,000 direct cost 
modules.  A feature of the modular grant is that no budget escalation is 
provided for future years, and all anticipated expenses for all years of the 
project must be included within the number of modules being requested.  Only 
limited budget information is required and any budget adjustments made by the 
Initial Review Group will be in modules of $25,000.

RESEARCH OBJECTIVES
 
Background

The past 20 years have seen an explosion in the understanding of how cancer 
cells work.  Specific molecules have been identified which cause the 
initiation and progressive growth of tumors.  From this work, a fundamental 
re-ordering of the approach to drug discovery and development for the 
treatment and prevention of cancer has emerged.  There is the opportunity to 
move away from screening agents by their effects on tumor cell growth, in 
vivo or in vitro, and targets that have been thoroughly exploited.  While it 
remains true that these methods might continue to be the basis for the 
development of clinically useful agents, these agents may not be the best 
lead compounds that effect a particular pathway of biologic importance 
specific for cancer establishment or progression.  Drugs discovered by these 
early methods have historically demonstrated clear limitations in clinical 
efficacy.  The hope is that drugs targeting new, specific molecular lesions 
in cancer cells will provide more effective therapy or prevention approaches, 
alone or in combination with other agents.  The focus of attention in this 
new approach to cancer drug discovery is a compound’s effect against a novel 
molecular target, or a target operating in a defined biochemical pathway, 
with the intent of causing a gain or loss in function to reverse, stop, or 
delay cancer progression.  The cancer cell selectivity of lead compounds 
should be enhanced by screens based on a novel target or a critical pathway 
that represents a true Achilles heel.

The evaluation of drugs in the clinic which have emerged from these types of 
approaches is beginning.  Examples would include the farnesyl transferase 
inhibitors (FTIs), protein kinase (PK) antagonists of various sorts, matrix 
metalloprotease inhibitors, and growth factor receptor or other effector 
antagonists (endothelin, tamoxifen, TRAIL, etc.).  It is striking that in 
this process the pharmaceutical industry has clearly seized a defining role 
in expeditiously advancing potentially useful compounds to a clinical test.  
However, in each of the instances cited, the pioneering studies on the 
targets to which these drugs are directed occurred largely (if not 
exclusively) in the academic sector.

Objectives and Scope

The goal of this PA is to provide the means for investigators to generate 
preliminary data leading to the discovery and validation of molecular targets 
for cancer prevention or treatment intervention which can be developed into 
drug discovery assays.  Identification of a potential target might present 
varying degrees of difficulty, but validation (an indication of a target’s 
predictive capacity to aid in the selection of clinical drugs) is apt to be 
uniformly more problematic.  Leads for many existing clinical drugs were not 
discovered through the use of  macro-molecular targets but rather through in 
vivo or in vitro anti-proliferative assays.  Accordingly, the cornerstone of 
this effort is the validation of targets of demonstrated importance.  
However, the exploratory/development grants, herein described, should be 
projects that seek preliminary data in the identification or validation of 
molecular targets or their development into a screening tool.  Approaches and 
projects appropriate for this PA should be in three general areas as follows:

First, investigative activities establishing a molecule as a potential cancer 
drug discovery target can have as its focus any aspect of early dysplasia or 
cancer cell biology that may reveal a vulnerability in the cancer cell.  
These might include cell cycle checkpoints, DNA repair, cell stress, or cell 
death pathways; cassettes of altered transcription factor activity; or 
activation of pathways allowing cell growth in hypoxic or hypo-vascularized 
conditions.  Oncogenic viral targets also would be appropriate.  In fact, any 
difference between a cancer and normal cell could potentially be exploitable 
as a therapeutic maneuver.  Modern science has afforded numerous 
opportunities to demonstrate the likely value of this approach.  These 
include: (1) engineered animals of various sorts (transgene-expressing, 
knock-out, etc.);  (2)  smart  assays designed to give information, not only 
about phenotypic alteration, such as growth arrest or cell death, but also 
about the effect on particular molecular targets of pathways known or 
suspected to have biological relevance to cancer;  (3) array technology, 
where the action of a candidate drug lead against its target can be placed 
rapidly in the context of expected action against other cellular and indeed 
organ-specific molecules; and (4) cancer gene discovery programs, such as the 
Cancer Genome Anatomy Project (CGAP) ( http://www.ncbi.nlm.nih.gov/CGAP/ ), 
which has identified numerous mutational sites in cancer cells, some of which 
are possibly unique to specific types of cancer.  Accordingly, a requirement 
is to establish that a molecular target likely affects important aspects of 
cancer cell function.

Second, the validation of new molecular targets, with the intent of 
discovering new agents for the treatment or prevention of cancer, is an 
important and necessary activity.  At present, science appears to offer too 
many targets.  Therefore, projects should focus on determining which of these 
numerous potential defects are sites of critical vulnerability which could be 
exploited for intervention.  Ideally one would expect to demonstrate that 
manipulation of the target function would cause a phenotypic change in the 
cancer cell.  Clearly if a prime target is fully validated, such that the 
target can be used to totally exploit a unique difference between a healthy 
and a cancerous cell, control of cancer would then only await the discovery 
of a drug molecule through a systematic screening and/or drug design program; 
in real laboratory experience, validation occurs in stages or degrees.  
Demonstration of some phenotypic or functional change that is desirable, such 
as elimination or reversal of dysplasia, tumor shrinkage or change in a 
validated surrogate marker, would provide evidence of the importance of a 
target.  Approaches to target validation might involve the use of antisense 
or engineered animals, such as transgene-expressing or gene knock-outs.  
Small, bioactive molecules, obtained either from natural products libraries 
or from chemical libraries, may be used as ligands to select and validate 
proteins from arrays.  If an investigator chooses to utilize crude extracts 
of natural products, as from the NCI Active Repository, expertise must be 
available for chemical fractionation of the extracts.  Thus, validation can 
be conceptualized as a series of milestones.   A proposal to reach validation 
milestones could be responsive to this PA.  There are many good rationales 
for selecting targets, but validation requires considerable imagination and 
skill on the part of the investigator.  Therefore, also responsive to this PA 
would be an insightful and clever validation of a target suggested by others 
as a possible intervention point.  While it is true that the ultimate 
validation can only come from a successful clinical trial, having information 
on the importance of the target prior to the trial should provide important 
feedback in case therapies are ineffective.

Third, the target system should be amenable to conversion into a screen for 
effectors of the target’s function (at minimum on a laboratory scale), or the 
molecular structure determined through biophysical techniques as a prelude to 
drug discovery studies .  These aspects are critical components which would 
form the thrust of any molecularly focused drug discovery effort.  The 
practical nature of drug discovery research is of high importance.  While the 
desirability of this approach might seem obvious, the tools for accomplishing 
this task are only now becoming routinely available.  These include sequence 
information defining the primary structure of relevant target proteins or 
other macromolecules; expression vectors for their large scale production; 
biophysical (e.g. X-ray and NMR) and computational techniques to allow the 
determination of three-dimensional structure; advances in screening 
technology to allow ever increasing speed and efficiency in assessing large 
numbers of candidate structures; and combinatorial chemistry to generate 
large numbers of candidate drug structures.

SPECIAL REQUIREMENTS

Patent Coverage.  Since the discovery of new targets, assays and improved 
anticancer treatments is the objective of this effort and since transfer of 
intellectual property to industrial laboratories for extended developmental 
purposes is facilitated by the existence of adequate patent coverage, it is 
essential that applicants provide plans to assure such coverage.  Each 
applicant must therefore provide a detailed description of the approach to be 
used for obtaining patent coverage and for licensing where appropriate, in 
particular where the invention may involve investigators from more than one 
institution.  Procedures must be described for resolution of legal problems 
should they arise.  Your attention is drawn to P.L. 96-517 as amended by P.L. 
98-620 and 37 CFR Part 401.  Instructions were also published in the NIH 
Guide for Grants and Contracts, Vol. 19, No. 23, June 22, 1990.

A formal statement of patent procedures and plan for transfer of materials 
embodying intellectual property to other parties as well as a detailed 
description of procedures to be followed for resolution of legal problems 
which may develop, signed and dated by the organizational official authorized 
to enter into intellectual property arrangements for each applicant and 
collaborators, if any, must be developed.  The signed agreement must be 
submitted prior to award to Dr. John Beisler at the address provided at the 
GCOB web site,  http://dtp.nci.nih.gov   (On the panel, left side, click on 
"Funding", then scroll down to "Staff").

Applicants proposing to access the Natural Products Repository of the NCI 
must obtain and execute the Natural Products Repository Material Transfer 
Agreement prior to receiving an award.  Similarly, applicants proposing to 
access the synthetic repository of the NCI must obtain and execute the 
synthetic Material Transfer Agreement prior to receiving an award.  These 
agreement forms are available at  http://dtp.nci.nih.gov.   (On the panel, 
left side, click on "Organization", select "Natural Products Branch", select 
"Natural Products Repository", then scroll down to and select "Material 
Transfer Agreement").   For information concerning the NCI synthetic or 
natural product repositories go to the Developmental Therapeutics web site, 
http://dtp.nci.nih.gov  (On the panel, left side, click on "Samples and 
Services").
	
For applications involving natural products, the applicant must provide a 
formal statement signed by an authorized representative of the applicant 
institution which assures that an equitable portion of royalties or profits 
arising from drugs discovered, if any, will benefit indigenous peoples, 
research collaborators, research institutions or governmental entities as 
appropriate, in the country of origin of the natural product sample from 
which the drug was derived.  Plans for the procurement of proper collection 
and export permits must be provided.  The signed document must be submitted 
prior to award to Dr. Gordon Cragg at the Developmental Therapeutics Program 
web site, http://dtp.nci.nih.gov  (On the panel, left side, click on 
"Organization", select "Natural Products Branch" then click on "Organization/ 
Staff Directory").

A plan must be developed for disposition of natural products samples, 
chemical libraries, etc.  The signed document must be submitted prior to 
award to Dr. John Beisler at the address provided at the GCOB web site, 
http://dtp.nci.nih.gov   (On the panel, left side, click on "Funding", then 
scroll down to "Staff").

The four documents listed above will not be included with review material, 
and therefore, will NOT be required at the time of application.  However, 
awards will not be made until they are received and approved by NCI.  

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 subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving
human subjects, unless a clear and compelling rationale and justification is 
provided 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 
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical 
Research," which have been
published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and 
in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 
1994, available on the web at the following URL address: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

Investigators may also obtain copies of the policy from the program staff 
mentioned in the GCOB web site, http://dtp.nci.nih.gov  (On the panel, left 
side, click on "Funding", then scroll down to "Staff").

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.

As part of the scientific and technical merit evaluation of the research 
plan, reviewers will be instructed to address the adequacy of plans for 
including children as appropriate for the scientific goals of the research, 
or justification for exclusion.

LETTER OF INTENT
 
Prospective applicants are asked to submit, by June 6, 2000, a letter of 
intent that includes a descriptive title of the proposed research, name, 
address, and telephone number of the Principal Investigator, identities of 
other key personnel and participating institutions, and 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 subsequent applications, the information allows NCI staff to 
estimate the potential review workload and to avoid conflict of interest in 
the review. 
 
The Letter of Intent is to be sent to a program representative listed under 
INQUIRIES by the letter of intent receipt date listed in the heading of this 
PA.
 
APPLICATION PROCEDURES

Applicants must use the research grant application form PHS 398 (rev. 4/98).  
Alternatively, NIH intramural project applicants must follow the directions 
below under the section heading:   Additional Instructions for NIH Intramural 
Project Applicants".  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:  [email protected].  PHS 398 application kits are also 
available at:  http://grants.nih.gov/grants/funding/phs398/forms_toc.html.

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 Internet sites.  Reviewers are cautioned that their anonymity may be 
compromised when they directly access an Internet site (see  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-004.html).

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $100,000 per year, including Facilities and 
Administrative (F&A) costs awarded to a collaborating institution. 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 key 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 if applicable and the NIH policy for graduate student 
compensation in developing the budget request.

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 key personnel, 
and the role on the project. 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.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

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.
SPECIAL INSTRUCTIONS FOR ALL APPLICANTS

The PA title, MOLECULAR TARGET DRUG DISCOVERY FOR CANCER:   EXPLORATORY 
GRANTS, and number of this PA must be typed on line 2 of the face page of the 
application form and the YES box must be marked.

The plans below, if appropriate for the proposed work, should be included in 
the application after the LITERATURE CITED section.  Formal agreements signed 
by an authorized representative of the applicant institution will be required 
before award.

o    A plan for patent coverage and licensing; for transfer of materials 
embodying intellectual property to other parties;  for resolution of legal 
problems should they arise.

o    A plan for an assurance to return benefits to the country of origin in 
the use of natural products.

o    A plan for the disposition of natural products samples and chemical 
libraries.

The completed original application and three legible copies must be sent or 
delivered 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 signed photocopy of the application 
must also be sent or delivered to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8062, MSC 8239
Bethesda, MD  20892-8239
Rockville, MD  20852 (for express/courier service)

Applications must be received by July 18, 2000.  If an application is 
received after that date, it will be returned to the applicant without 
review.  The Center for Scientific Review (CSR) will not accept any 
application in response to this PA that is essentially the same as a research 
project application 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 an application must follow the guidance in the PHS Form 398 
application instructions for the preparation of revised applications, 
including an introduction addressing the previous critique.

ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS

The research grant application form PHS 398 (rev. 4/98) is also to be used by 
NIH intramural project applicants in applying for these grants.  Applications 
kits are available 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: 
[email protected]    For those applicants with internet access, the 398 kit 
may be found at http://grants.nih.gov/grants/funding/phs398/forms_toc.html.  
The PHS 398 application form should be used with the following modifications:

o  On the Face Page, fill out only items 1., 2., 3.(leave 3c. blank), 4 and 
5.  The remainder of the items should be left blank, and the application must 
not be signed by either the PI or an NIH Institute official. 

o  Do not submit "Other Support", Checklist", "Personnel Report", or 
"Personal Data" pages.

o  The PI must obtain the approval of the NIH Institute Scientific Director 
for applying for collaboration, or for participating as a principal 
investigator, in the MTDD program under the terms and conditions of the PA.  
A copy of that letter of approval must be provided as part of a cover letter, 
addressed to the NCI Referral Officer, for the application.

o  The budget page should supply the time and effort for each project 
participant, but no other budget figures should be included.  The resources 
available for the project and the research environment should be carefully 
described, but no budget figures should be included.  The NIH Institute 
Scientific Director, as part of the letter of approval for participation, 
must verify that no more than $100,000 direct costs of intramural resources 
will be allocated to the project described in the application, and provide 
assurance that the conduct of the project will comply with the DHHS 
regulations for research involving human subjects (if applicable) and with 
the PHS policy on vertebrate animal research.

o   For NIH intramural applicants, a letter of approval must be submitted 
from their Institute Intramural Scientific Director to allocate resources to 
the project.  

o  Submit an unsigned, typewritten original of the application, and five 
photocopies to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8062, MSC 8239
Bethesda, MD  20892-8239
Rockville, MD  20852 (for express/courier service)

Do not send the application or any copies to the Center for Scientific 
Review.  NIH intramural project applications must be received by July 18, 
2000.  If an application is received after that date, it will be returned to 
the applicant without review.

REVIEW CONSIDERATIONS: Extramural Applications

Upon receipt, applications will be reviewed for completeness by CSR and for 
adherence to the guidelines by NCI.  Incomplete  applications will be 
returned to the applicant without further consideration.  

Applications that are complete will be evaluated for scientific and technical 
merit by an appropriate peer review group convened by the Division of 
Extramural Activities of the NCI in accordance with the review criteria 
stated below.  As part of the initial merit review, a process will be used by 
the initial review group in which applications will receive a written 
critique and 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, assigned a priority score, and receive a 
second level review by the National Cancer Advisory Board.

Review Criteria

The goals of NIH-sponsored research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
Within this framework, the specific goals of this PA are to provide support 
to enable investigators without preliminary data to discover and/or validate 
new molecular targets with the potential for developing assays for the 
discovery of new agents to treat or prevent cancer.  For example, these 
exploratory/ developmental grants may be to identify or characterized (de 
novo, or from the literature) a target, to generate data for a validation, or 
to develop a method to render a  validated target into a drug assay.  
Meritorious projects will include imaginative intervention points and 
insightful validation approaches, which overall will reveal an exploitable 
site of critical vulnerability.

The reviewers will comment on the five criteria listed below in their written 
critiques of the applications 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.  

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?  Is the proposed molecular target of importance to 
development and maintenance of the transformed phenotype?  Is the target new 
and not one which has been the object of other evaluative studies?  What is 
the likelihood that assays using this target will lead to a new class of 
agents for the prevention or treatment of cancer? 

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 
alternate tactics?  How well has the applicant addressed the major goals of 
the PA: identification of a novel target, its validation as an intervention 
point, and assay development?  What is the likelihood that a high-throughput 
screen can be developed with the target?  Has the applicant designed an 
appropriate set of experiments to demonstrate a critical site of 
vulnerability in the cancer cell which can exploited for treatment or 
prevention?  If crude natural product extracts are proposed, are strategies 
for compound isolation and identification adequate?  If structural biology 
studies are proposed, are plans adequate for the production of materials and 
have appropriate collaborations been arranged?  If screening is proposed, are 
data handling procedures adequate, and is the assay validated and appropriate 
for large-scale or high throughput use?

Innovation:  Does the project employ novel concepts, approaches, or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies?  Will the approaches advance the use 
of new, validated molecular targets for new drug discovery?

Investigator:  Is the investigator appropriately trained and suited to carry 
out the project?  Is the research proposed appropriate to the experience 
level of the PI and other researchers (if any)?

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 valuable 
collaborative arrangements?

Additional Considerations

The initial review group will also examine: the appropriateness of the 
proposed budget and duration; the adequacy of plans to include both genders 
and minorities and their subgroups as appropriate for the scientific goals of 
the research and plans for the recruitment and retention of subjects; the 
adequacy of plans for including children as appropriate for the scientific 
goals of the research, or justification for exclusion; the provisions of 
human and animal subjects; and the safety of the research environment.

For intramural applications, all of the above applies except applications 
will not be reviewed for completeness by CSR, the proposed budget will not be 
reviewed by the review group.


 AWARD CRITERIA
 
Extramural applications recommended by the National Cancer Advisory Board will 
be considered for award based upon (a) scientific and technical merit; (b) 
program balance, including in this instance, sufficient compatibility of 
features to make a successful collaborative program a reasonable likelihood; 
and (c)  availability of funds. 

INQUIRIES
 
Written and telephone inquiries concerning this PA are encouraged.  The 
opportunity to clarify  any issues or questions from potential applicants is 
welcome.
 
Direct inquiries regarding programmatic issues in cancer treatment, to the 
appropriate individuals given in the GCOB web site:  http://dtp.nci.nih.gov/  
(On the panel, left side, click on "Funding", then scroll down to "Staff").  
Inquiries regarding access to the Natural Products Repository and inquiries 
regarding access to the Synthetic Compound Repository of NCI refer to the 
appropriate paragraph in the SPECIAL REQUIREMENTS section.

Direct inquiries regarding programmatic issues in cancer prevention to the DCP 
web site: http://dcp.nci.nih.gov/cb	

Direct inquiries regarding review issues to:

Ms. Toby Friedberg
Referral Officer
Division of Extramural Activities
National Cancer Institute
6116 Executive Boulevard, Room 8062, MSC 8239
Bethesda, MD  20892-8239
Rockville, MD  20852 (for express/courier service)
Telephone (301) 496-3428
Fax: (301) 402-0275
Email: [email protected]
	
Direct inquiries regarding fiscal matters to: 
 
Ms.  Kathleen Shino
Grants Administration Branch 
National Cancer Institute 
Executive Plaza South 243 				
Bethesda, MD  20892-7150
Telephone:  (301) 496-8635 
Fax: (301) 496-8601
Email: [email protected]

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 and contract 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.     		

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