MOLECULAR TARGET DRUG DISCOVERY FOR CANCER:  EXPLORATORY GRANTS

Release Date:  February 2, 2001

PA NUMBER:  PAR-01-045
 
National Cancer Institute

Letter of Intent Receipt Date:  May 17, 2001
Application Receipt Date:       June 14, 2001

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 (PA) replaces PAR-00-060, which was published in the 
NIH Guide on February 18, 2000.

PURPOSE

The National Cancer Institute (NCI) defines new, extraordinary research 
opportunities through stated goals in a "Bypass Budget".   Among the 
priorities of the 2001 and 2002 Bypass Budgets is a plan 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.  Current research in carcinogenesis has 
identified many enzymes, genetic lesions, and their cellular constituents 
associated with inhibition and progression of pre-cancers to invasive disease.  
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 a related 
initiative in molecular target drug discovery for cancer treatment and 
prevention utilizing an additional funding mechanism: Competing Supplements 
for existing NCI awardees 
(https://grants.nih.gov/grants/guide/pa-files/PAR-01-046.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 and for 2002 at 
http://plan2002.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.

This PA will expire on June 15, 2001 unless reissued.  NIH Grants policies 
apply to these awards.

RESEARCH OBJECTIVES
 
Background

The past 20 years have seen an explosion in the understanding of how cancer 
cells work.  Increasing knowledge of human carcinogenesis is providing many 
new opportunities for study of molecular targets modulated by drugs that might 
prevent cancer.  Most of the insights have resulted from an improved 
understanding of the genetic basis of carcinogenesis.  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 selective and less toxic 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 represent a true Achilles heel.  Some possible ways that 
preventive agents may modify molecular targets include interfering with tumor 
initiation by:  1) modifying carcinogen activation by enzymes responsible for 
activation or scavenging DNA reactive electrophiles or free radicals,
2) enhancing carcinogen detoxification processes by altering the activity of 
detoxifying enzymes,  3) repairing structural/functional genetic defects by 
enhancing endogenous DNA repair systems,  4) blocking tumor promotion and 
progression including altering the expression of genes involved in cell 
signaling, particularly those regulating cell proliferation, apoptosis and 
differentiation.

The evaluation of drugs in the clinic which have emerged from these types of 
approaches is beginning.  A recent example is the discovery of STI-571, a 
Novartis compound under investigation for the treatment of chronic myelogenous 
leukemia (CML) and other cancers.   STI-571 has been shown by Schindler et al. 
in Science 289, 1938 (2000) to target the Bcr-Abl fusion protein, a tyrosine 
kinase whose expression is considered to be the cause of CML.  Other examples 
which might be mentioned include the farnesyl transferase inhibitors (FTIs), 
protein kinase (PK) antagonists of various sorts, matrix metalloprotease 
inhibitors, and growth factor receptor or other effector antagonists 
(herceptin, endothelin, tamoxifen, TRAIL, etc.).  Recent cancer epidemiology 
and pharmacogenetic studies have suggested the importance of genetic 
polymorphisms affecting the ability to detoxify carcinogens, e.g., 
glutathione-S-transferase (GSTM1, GSTM2, GSTP1), N-acetyltransferase (NAT1, 
NAT2), cytochrome P450 (CYP450IAI), and steroid 5-alpha-reductase type II 
(SRD5A2).  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 one or more of 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, cell 
immortalization or cell death pathways; cassettes of altered transcription 
factor activity; activation of pathways allowing cell growth in hypoxic or 
hypo-vascularized conditions; events involved in angiogenesis, cell invasion 
and metastases; or strategies to modulate the immune system.  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 treatment and prevention 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 A. Beisler at the address provided below 
under INQUIRIES.

Applicants proposing to access the Natural Products Repository of the NCI must 
obtain and execute the Natural Products Repository Material Transfer Agreement 
(MTA) prior to receiving an award.  Similarly, applicants proposing to access 
the synthetic repository of the NCI must obtain and execute the synthetic MTA 
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 A. Beisler at the address provided below under INQUIRIES.

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.

MECHANISM OF SUPPORT 
 
The 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.   
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
R21 application submitted in response to this PA may not exceed TWO years.   
Although the size of award may vary with the scope of research proposed, it is 
expected that applications will stay within the budgetary guidelines for an 
exploratory/developmental project; direct costs are limited to $100,000 (four 
budget modules) per year unless the application includes consortium costs, 
including Facilities and Administrative (F&A) costs awarded to the 
collaborating institution, in which case the limit is $125,000 in direct costs 
(five modules) per year.  These grants are non-renewable and continuation of 
projects developed under this program must be through other grant mechanisms.   
The earliest anticipated award date is April 1, 2002.  

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 being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

ELIGIBILITY REQUIREMENTS 
 
These exploratory/developmental grant applications (R21) 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.  
Domestic applications may include international components.  Applications may 
also be submitted by 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.   

INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues in cancer treatment to:

John A. Beisler, Ph.D.
Developmental Therapeutics Program
National Cancer Institute
EPN  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:  beislerj@exchange.nih.gov

Direct inquiries regarding programmatic issues in cancer prevention:

Winfred F. Malone, Ph.D.
Chemopreventative Agent Development Research Group
National Cancer Institute
EPN  Room 200A
6130 Executive Boulevard
Bethesda, MD    20892-7322
Rockville, MD   20852 (for express/courier service)
Telephone: (301) 594-0460
FAX: (301) 402-0553
Email:  malonew@mail.nih.gov

Direct inquiries regarding fiscal matters to: 
 
Ms. Barbara A. Fisher
Grants Administration Branch 
National Cancer Institute 
Executive Plaza South 243 
Bethesda, MD  20892-7150
Telephone:  (301) 846-1015 
Fax: (301) 846-5720
Email:  fisherb@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 May 17, 2001, 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 application, the information that list contains allows NCI staff to 
estimate the potential review workload and plan the review. 
 
The Letter of Intent should be sent to Dr. John A. Beisler at the address 
listed under INQUIRIES. 
 
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 applicant, reviewers and NCI 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.  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 301/710-0267;  E-mail:  grantsinfo@nih.gov
.  The title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.  For 
those applicants with internet access, the 398 kit may be found at: 
https://grants.nih.gov/grants/forms.htm  

Applicants are strongly encouraged to call program contacts listed in 
INQUIRIES above with any questions regarding the adherence to the guidelines 
of their proposed project to the goals of this PA.

SPECIFIC INSTRUCTIONS 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 $100,000 per year ($125,000 if there are 
consortium/contractual costs).  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 4 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 https://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 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 all 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 year to year 
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
https://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 expedite the review process, at the time of submission, send two additional 
signed photocopies of the application to:

Ms. Toby Friedberg
Referral Officer
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

Applications must be received by the receipt date at the beginning of this 
program announcement.  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.

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.

o    A signed Materials Transfer Agreement (MTA) if products from the Natural 
Products Repository will be obtained.

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 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) 710-0267, E-mail: grantsinfo@nih.gov    
The title and number of the PA must be typed on line 2 of the face page of the 
application form and the YES box must be marked.   The 398 kit may also be 
found on the internet at 
https://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 
when applying 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 8109, 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: 

Upon receipt, applications will be reviewed for completeness by CSR 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 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 all 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 five criteria to be used in the evaluation of grant applications are 
listed below:

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.  

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?  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? 

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 
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, or 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?

3.  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 or technologies?  Will the 
approaches advance the use of new, validated molecular targets for new drug 
discovery?

4.  Investigator.  Is the investigator appropriately trained and suited to 
carry out this work?  Is the research 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 
valuable collaborative arrangements?  Is there evidence of institutional 
support?

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
 
Applications will compete for available funds with all other recommended 
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. 

SCHEDULE

Letter of Intent Receipt:         May 17, 2001
Application Receipt Date:         June 14, 2001
Review by NCAB Advisory Board:    February 2002
Earliest Anticipated Start Date:  April 1, 2002

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 
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  
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html   
A complete copy of the updated Guidelines is available at  
https://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:  https://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

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 
https://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, 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 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.

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