MOLECULAR TARGET DRUG DISCOVERY FOR CANCER

Release Date:  February 16, 2000

RFA:  CA-00-002
 
National Cancer Institute

Letter of Intent Receipt Date:  June 6, 2000
Application Receipt Date:       July 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 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, NCI, and the Chemoprevention Agent 
Development Research Group,  the Division of Cancer Prevention, NCI  invite 
cooperative agreement applications 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. 

Projects are acceptable at all stages of development, including mature 
projects as well as novel insights at an early investigational stage.  
However, the cooperative agreements, herein described, should be projects that 
are more developed and comprehensive.  In addition to this RFA, the NCI 
announces the following three related program announcements in molecular 
target drug discovery for cancer treatment and prevention:  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, Exploratory/Development Grant (R21) awards 
(see http://grants.nih.gov/grants/guide/pa-files/PAR-00-060.html)
for pilot projects for which preliminary data are lacking that would make the 
project competitive for a regular research grant, Competing Supplements for 
existing NCI awardees
(see http://grants.nih.gov/grants/guide/pa-files/PAR-00-062.html), which can be 
used to extend the goals of active grants to include studies related to drug 
discovery.  Also see the HomePages 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 RFA.  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 Request for Applications (RFA) is to reorganize the  front 
end  or gateway to drug discovery.  Investigators are being asked to identify 
a novel molecular target, to validate the target as a basis for cancer drug 
discovery, and 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 RFA would support an investigator to validate a target and 
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.  
Once targets are identified and validated, they will be developed into high-
throughput screens by the applicant or through collaborative arrangements, 
potentially using NCI contract research resources, with appropriate safeguards 
for intellectual property.  The RFA requires that the proposed target (s) in 
each application be novel and not addressed by drugs already approved for 
clinical use.

A special feature of this Molecular Target Drug Discovery (MTDD) effort will 
be the ability for grants funded through this RFA to be eligible for 
administrative supplements to add structural biology studies, create targeted 
libraries, acquire pre-existing libraries, or screen compounds following 
negotiation of appropriate collaboration agreements.  These activities may of 
course be a part of the initial application if the Principal Investigator (PI) 
has data convincing to the peer review committee that the proposed target has 
sufficient validation.  Alternatively, awardees will have access to NCI-
supported contract research resources that may facilitate their studies.

Applications will be submitted to the NIH and will be reviewed by the NCI 
according to the criteria established for this RFA 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 RFA, 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 
 
Applications 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 RFA, 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 awards for non-NIH 
applicants will be a cooperative agreement (U01), an "assistance" mechanism 
(rather than an "acquisition" mechanism) in which substantial NIH scientific 
and/or programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NCI’s role 
is to support and/or stimulate the recipient"s activity by working jointly 
with the award recipient as a partner, but it is not to assume direction, 
prime responsibility, or a dominant role in the activity.  Details of the 
responsibilities, relationships and governance of the study to be funded under 
a cooperative agreement are discussed later in this document under the section 
"Terms and Conditions of Award." There is no intent, real or implied, for NCI 
staff to direct an awardee’s activities or to limit the freedom of 
investigators.  Assistance via cooperative agreement differs from the research 
project grant in that the government component (NCI) awarding the cooperative 
agreement anticipates a partnership relationship that will enhance the 
efficiency and effectiveness of an awardee’s efforts.

The total project period requested for applications submitted in response to 
this RFA may not exceed four years.  The earliest anticipated award date is 
April 1, 2001.  Because the nature and scope of the research proposed in 
response to this RFA may vary, it is anticipated that the size of awards will 
vary.  The number of awards and the level of support depend on receipt of a 
sufficient number of applications of high scientific merit.  Although this 
program is provided for in the financial plans of the NCI, awards pursuant to 
this RFA are contingent upon the availability of funds for this purpose.  
Unless otherwise noted, all NIH grants policies apply.

No funds from the amount set aside for this RFA will be used to support 
intramural projects from NIH.  For further budget information pertaining 
specifically to NIH intramural applications, see section  APPLICATION 
PROCEDURES  below regarding  Additional Instructions for Intramural Project 
Applicants. 

This RFA is a one-time solicitation.  To enable a continuing flow of 
applications to this initiative, NCI anticipates continued support in the 
future through a Program Announcement with NCI review (PAR). 

FUNDS AVAILABLE

The NCI has budgeted $3 million total costs (direct plus facilities and 
administrative costs) for the first year of funding, subject to the 
availability of funds.  It is expected that NCI will make 8-10 awards for 
periods up to four years.  The number of awards and individual level of 
support are dependent on the receipt of a sufficient number and diversity of 
applications with high scientific merit.  Program balance and diversity of 
topics will be factors in selecting applications for award.
 
Budget requests should be justified and commensurate with the needs of the 
project.  Those in excess of $500,000 total costs for the first year must be 
carefully justified, and the projects must be highly meritorious.  Annual 
budgets for years two to four should not exceed the first year budget plus a 
3% yearly increase.  Equipment needs, especially in future years, must be well 
justified.
 
Although no funds from the amount set aside for this RFA will be used to 
support intramural projects, NIH intramural project applicants must verify 
that the amount of the resources allocated from intramural sources does not 
exceed $300,000 direct costs.  For further budget information pertaining 
specifically to NIH intramural applications, see   APPLICATION PROCEDURES , 
below regarding  Additional Instructions for NIH Intramural Applicants."

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 RFA is 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.  At minimum, a target 
should be identified (de novo, or from the literature), a validation plan 
outlined, and a conception of how the validated target could be developed into 
a drug assay.  Approaches and projects appropriate for this RFA 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 RFA.  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 RFA 
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.

A Molecular Target Analysis Group made up of each of the MTDD Principal 
Investigators, as well as ad hoc members, and NCI Extramural Program Staff, 
will meet at least twice yearly to evaluate targets selected from MTDD 
efforts.  The Molecular Target Analysis Group will recommend criteria for 
defining and validating appropriate drug discovery targets as well as 
determining when a putative target is appropriate for development into a high-
throughput screen.  The NCI will facilitate the identification of sources and 
establish distribution systems for compound libraries, database resources, and 
information systems to disseminate non-proprietary data and information to the 
research community.  Access to NCI contract research resources will be a 
distinguishing feature of MTDD awards.  To facilitate communication among the 
MTDD participants, NCI will establish and maintain an Internet-based mechanism 
for rapid data and document transmission and electronic communications.  In 
order to assure that novel ideas and inventions are rapidly developed to the 
benefit of the public, it is understood that intellectual property protection 
may be needed for some of the data and materials resulting from grantee 
labors.

Resources potentially available to MTDD grantees, if not a part of the initial 
individual application, include but certainly are not limited to the 
following:

o  Expression of Target:  Successful applicants whose program requires 
production of quantities of expressed target protein for either structure 
elucidation and/or assays will be eligible for supplements to achieve this 
goal.  This will be accomplished either through production at their own 
institution or at a contract research facility using constructs emanating from 
the applicant’s laboratory.  Authority for granting these supplements will 
rest with NCI Program staff. 

o  Structural Analysis of Target:  Applicants will be encouraged to describe 
in the application, when it exists, ongoing relationships with structural 
biologists who will be responsible for structure determination using relevant 
physical techniques such as X-ray crystallography or NMR.  At a point in the 
progress of a project when structural analysis might seem appropriate, funds 
for support of biophysical studies may be requested.  Lacking that initial 
collaboration, grantees could obtain supplemental funding through, for 
example, a consortium arrangement with a structural biologist.  When the 
opportunity for structural analysis presents itself, funds will be flexibly 
available to stimulate this interaction as needed.  Authority for 
implementation of the supplements will rest with NCI Program staff. 

o  Access to Chemistry/Screening:  Following definition of a candidate assay 
relevant to a target, efforts to create libraries of compounds and conduct 
screening activities that are based on the target’s structure may be 
undertaken.  This effort could use contract research resources available to 
NCI, but would be paired by NCI staff in their management with the MTDD 
investigator.  In the event that an MTDD project produces its own libraries, 
these would remain the property of the originator.  NCI may take the lead in 
developing specific "made to order" libraries or libraries may emerge from 
existing collections available to NCI.  All new libraries funded from an 
outside source under the overall umbrella of an MTDD grant will be the 
property of the originating PI, but may be offered to additional MTDD grantees 
or other peer-reviewed, NCI-sponsored drug discovery efforts under appropriate 
Material Transfer Agreements.  Screening might also be supported by contract 
research resources in the event it cannot be done in the originating PI’s 
laboratory, or it might be conducted by supplementation of the award to 
include the cost of screening.  Authority for implementation of chemistry or 
screening efforts would rest with NCI Program staff.

o  Access to Preclinical Drug Development:  A key issue in early compound 
development may be the toxicologic, pharmacologic and/or pharmaceutic 
properties of a lead.  NCI-directed contract research resources may be made 
available to assess initial pharmacologic or pharmaceutical features of leads, 
or of subsequent versions of the lead that may have included efforts to 
optimize in vivo efficacy, pharmacology or formulation attributes.  Advice 
concerning the suitability of the molecule(s) for these studies may be sought 
from the NCI Program Director.

SPECIAL REQUIREMENTS

1. Definitions 

ARBITRATION PANEL:  A panel that is formed to review any scientific or 
programmatic disagreement, within the scope of the awards supported under this 
RFA, between U01 awardees or NIH intramural projects and the NCI.  The panel 
will be composed of three members: one selected by the Molecular Target 
Analysis Group (excluding the NCI staff representatives) or the individual U01 
awardee or NIH intramural program in case of an individual dispute, a second 
member selected by NCI staff, and a third members selected by the prior 
selected members.  For U01 awardees, this special arbitration procedure in no 
way affects the awardee’s right to appeal an adverse action that is otherwise 
appealable in accordance with the PHS regulations at 42 CFR part 50, Subpart D 
and HHS regulation at 45 CFR Part 16.

AWARDEE:  The institution to which the MTDD project (U01) is awarded.

COOPERATIVE AGREEMENT (U01):  An  assistance  mechanism, rather than an 
 acquisition  mechanism, in which substantial NCI scientific and/or 
programmatic involvement is anticipated during performance of the activity.  
Under the cooperative agreement, the NCI purpose is to support and/or 
facilitate the activity by involvement in, and otherwise working jointly with, 
the awardee in a partner role, but NCI is not to assume direction, prime 
responsibility, or a dominant role in the activity.

DRUG:  In the context of this RFA, a term used broadly to encompass synthetic 
agents, natural products and biological products designed to treat and/or 
prevent cancer.
 
INTELLECTUAL PROPERTY (IP):  Inventions which may result from the discovery of 
new targets, design of new assays or models, or discovery of new agents 
effective for the treatment or prevention of cancer.  However, works of 
authorship, which can be copyrighted, and trademarks are also included.

MOLECULAR TARGET DRUG DISCOVERY (MTDD) awards:  Cooperative agreements or NIH 
intramural projects which are designed to discover, validate, and utilize as a 
screening model, new molecular targets that are important for cancer and 
exploitable for new drug discovery.

MOLECULAR TARGET: For the purpose of this RFA, an entity, which could be a 
protein, a receptor or enzyme, or a cellular process or a pathway, that is 
essential for the establishment and maintenance of the cancer phenotype.  
Within the context of this RFA, molecular targets to be investigated should 
not include those already exploited by clinically available drugs.

PRINCIPAL INVESTIGATOR: The scientist who is designated by the applicant 
institution or NIH intramural laboratory to direct the MTDD project.  The PI 
will assume responsibility and accountability to the applicant institution and 
the NCI for the performance and proper conduct of the MTDD project in 
accordance with the terms and conditions specified in this RFA.  

NCI  PROGRAM OFFICIAL:  The senior staff member of the Grants and Contracts 
Operations Branch, Developmental Therapeutics Program, Division of Cancer 
Treatment and Diagnosis, or the Chemoprevention Agent Development Research 
Group, the Division of Cancer Prevention, who provides leadership and guidance 
for the overall MTDD Program within NCI, maintains overall scientific balance 
for the Program, ensures that it is consistent with the NCI mission of 
treatment or prevention, and performs the normal stewardship activities. 

NCI  PROGRAM SCIENTIST:  A science administrator of the NCI extramural staff, 
appointed after award by the NCI Program Official, who participates as a 
member of an MTDD Group, interacts scientifically with the Group and 
facilitates the role of the NCI as a partner in the Group.

MOLECULAR TARGET ANALYSIS GROUP:  A committee which will include the PI or 
their designated representatives from each U01 or NIH intramural project 
selected under this RFA.  NCI Program Scientists will serve as non-voting 
members.  Its purpose will be to apply its collective knowledge to accelerate 
the pace of identification of new molecular targets for drug discovery and to 
exchange information among its members.  The Molecular Target Analysis Group 
and their collaborators will participate in recommending guidelines and 
standards for the discovery and validation of new targets,

II.  Other Considerations

A.  The Principal Investigator or designated representative should plan to 
attend twice yearly meetings of the Molecular Target Analysis Group.

B. The Principal Investigator must state in the application a willingness to 
participate in the Molecular Target Analysis Group and provide a commitment to 
sharing data and reagents as recommended by the NCI staff.

C.  The Principal Investigator must state in the application a willingness to 
accept participation of NCI staff during performance of the award as outlined 
below under  NCI Extramural Staff Responsibilities .

D.  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.  Also, 
according to the terms of this RFA, the NCI staff may recommend that reagents 
and assays, which may be considered IP, be transferred to another party for 
assay development or screening purposes.  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.  A plan 
should be developed for transfer of materials embodying intellectual property 
to other parties upon recommendation by NCI.  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 be returned to 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., in conformance with  Terms and Conditions of Award  below.  
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.

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.    

E.  An NIH intramural scientist (IMS) may serve as a PI on a project, and for 
supported projects an IMS or their designated representative will serve on the 
Molecular Target Analysis Group for recommending guidelines and standards for 
the discovery and validation of new targets.  However, an IMS may not receive 
salary, equipment, supplies, or other remuneration from this RFA.  The IMS 
must obtain approval of their respective NIH Institute Scientific Director to 
allocate resources to the project.  This letter must specify that no more than 
$300,000 direct costs of intramural resources will be allocated to the project 
and provide assurance that the conduct of the project will comply with the 
Department of Health and Human Services (DHHS) regulations for vertebrate 
animal and human subjects research.  The participation of an IMS is 
independent of and unrelated to the role of the NCI Program Official as 
described below in  Terms and Conditions of Award .

III. TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the U01 award 
statement, and will be provided to the PI and awardee institutional official 
at the time of award or to the PI of the NIH intramural project and NIH 
Institute Scientific Director at the time of selection for participation.  
Failure to abide by any of the TERMS AND CONDITIONS OF AWARD pertaining to 
awardee responsibilities as stipulated, may result in reduction of funding, 
withholding of support, or suspension or termination of award.

These special Terms of Award are in addition to, and not in lieu of, otherwise 
applicable OMB administrative guidelines, HHS Grant Administration Regulations 
at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration 
policy statements.  (Part 92 applies when state and local government are 
eligible to apply as a  domestic organization .) 

A. The administrative and funding instrument used for the non-NIH intramural 
applicants is the cooperative agreement (U01), an  assistance  mechanism 
(rather than as  acquisition mechanism) in which substantial NIH scientific 
and programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH purpose 
is to support and/or stimulate the recipient’s activity by involvement in and 
otherwise working jointly with the award recipient in a partner role, but it 
is not to assume direction, prime responsibility, or a dominant role in the 
activity.  Consistent with this concept, the dominant role and prime 
responsibility for the activity supported by a cooperative agreement resides 
with the awardee for the project as a whole, although specific tasks and 
activities in carrying out the studies will be shared by the awardee and NCI.  
NIH intramural project applicants will be supported by intramural resources.

B. Awardee Rights and Responsibilities

1.  The PI is the scientist who is designated by the awardee institution or 
NIH intramural laboratory to direct the MTDD project.  The PI will have 
primary authority and responsibility to define objectives and approaches, and 
to plan and conduct the proposed research. The PI will assume responsibility 
and accountability to the awardee institution and to the NCI for performance 
and proper conduct of the research in accordance with the TERMS AND CONDITIONS 
OF AWARD.

2.  The PI or designated representative will serve as a voting member of the 
Molecular Target Analysis Group and will attend meetings as scheduled.

3.  As stated in the RFA, the PI will be responsible for accepting the NCI 
molecular target goals, procedures, and policies.  Included, but not limited 
to, would be the transfer of molecular target and screening assays to a third 
party, such as an NCI contract-based resource, for the purpose of developing 
and/or utilizing high-throughput screening.

4.  Awardees will retain custody of, and have primary rights to, data 
developed under awards, subject to Government rights of access consistent with 
current HHS, PHS, and NIH policies.  Under the terms of OMB Circular A-110, 
data generated by grantees is now subject to the Freedom of Information Act.  
Assays and use of novel molecular targets developed under the U01s may be 
considered unique research resources.  The policy of the PHS is to make 
available to the public results and accomplishments of activities that it 
funds.  All awardees must adhere to PHS policy for distribution of unique 
research resources produced with PHS funding, which was published in the 
Federal Register on December 23, 1999 [64 FR 72090] and is available on the 
Internet at: http://www.ott.nih.gov/policy/rt_guide_final.html.  Publication or oral 
presentation of work done under this agreement will require appropriate 
acknowledgment of NCI support:  see Acknowledgment of Federal Funding (Section 
507) in the Notice of Legislative Mandates Contained in the FY2000 Omnibus 
Appropriations 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-010.html .  
Dissemination of information or synthetic or natural substances supplied by 
NCI will require clearance by NCI to assure conformity with existing 
confidentiality agreements with suppliers.

5.  Possessory rights of physical materials, such as natural product samples 
and chemical libraries acquired during the course of the research, rests with 
the applicant.  For samples governed by a Materials Transfer Agreement (MTA), 
disposition will be determined in consultation, and with approval of, NCI.   
Transfer of samples to other parties or collaborators can only be done if the 
other party(ies) agree to the MTA through being a signatory of the MTA.  Prior 
to award the applicant must formulate a policy for final disposition of the 
samples and ownership rights in the event that the samples are transferred to 
other parties who use them to make discoveries.  

6.  In order that samples be fully evaluated for anticancer potential after 
the awardee has concluded its evaluation, but before the samples are 
transferred to other parties for evaluation in other therapeutic areas, it is 
requested that the awardee provide lists of completed samples to an NCI 
Program Scientist, who may facilitate additional biological evaluation in 
NCI’s contract-based screening facilities or at an additional testing resource 
of mutual agreement to NCI and the awardee.

7.  The NCI recognizes that most countries retain interest in samples 
collected within their domains.  In the event that an applicant may propose 
study of natural products from foreign sources, a formal statement of 
agreement, prior to an award, must be provided to NCI, signed by an authorized 
representative of their institution and that of their collaborators, if any, 
for equitable return of benefits such as profits or royalties derived from 
discoveries supported by this award to indigenous peoples, research 
collaborators, cooperating institutions or governmental entities in the 
countries of origin, as appropriate to their contributions.

C.  NCI Extramural Staff Responsibilities

1.  The NCI Program Official will select an NCI Program Scientist, from the 
extramural but not the intramural staff, for each MTDD following award.  NCI 
will participate as a non-voting member of the Molecular Target Analysis Group 
and will be represented by Program Scientists.  During performance of the 
award, through the NCI Program Scientist, the NCI may provide appropriate 
assistance by participating in the design of activities.  In all cases, the 
role of NCI will be to assist and facilitate and not to direct activities.

2.  The NCI Program Scientist, as well as any other MTDD group member, may 
assist in research planning, may suggest studies within the scope of the 
MTDD"s objectives and research activities, may present to the MTDD 
experimental findings from published sources or from contract projects in 
support of these suggestions, may participate in the design of experiments 
agreed to by the MTDD, may advise in the selection of sources for resources, 
may advise in management and technical performance, and may participate in the 
analysis of results.  However, the NCI Program Scientist will not conduct 
laboratory studies.

3.  Upon recommendation of the NCI Program Scientist, NCI may utilize its drug 
development resources in support of activities when such resources may be 
required on an occasional basis.  The following is a list or resources that 
may be supplied if they become desirable during performances, are not 
anticipated as a continuing need, and are readily available.

a.  Reference compounds for standardization of test systems, as analytical 
standards, and for related purposes.
b.  Needed resources such as test materials and information.  
c.  Data from testing conducted in resource contract laboratories.
d.  Laboratory testing capacity in NCI’s current contract-based resources.
e.  Searches of computer files of materials, chemical structures and 
biological activity.  Information provided will be restricted by any 
confidentially agreement between the Government and suppliers of such 
materials or information. 
f.  Experimental animals and cultured cells, if available, to projects which 
do not require these items on a regular basis.  Projects which require animals 
and cells on a regular basis must budget these items in the application.	    

D.  Collaborative Responsibilities

Molecular Target Analysis Group:

NCI Program Scientists, the Program Official and Principal Investigators for 
U01 awards and NIH intramural projects will form a Molecular Target Analysis 
Group as defined below.  An arbitration system, as detailed below, will be 
available to resolve any disagreement which may arise between NIH Program 
Scientists and the members of the Molecular Target Analysis Group.

The  Molecular Target Analysis Group will be composed of the PI from each U01 
or NIH intramural project or their designated representatives plus non-voting 
representatives selected by the voting members.  The NCI Program staff will 
attend as non-voting members.  A Chair, not from the NCI extramural staff, 
will be selected by the  Molecular Target Analysis Group.

The  Molecular Target Analysis Group or NCI may, when it is deemed to be 
necessary, invite additional, ad hoc, non-voting  advisors to the meetings. 

The  Molecular Target Analysis Group will meet at least twice annually.  One 
meeting will be in the Bethesda area and the other at a time and place agreed 
upon by the  Molecular Target Analysis Group and the NCI.

A planning meeting of the Molecular Target Analysis Group will be convened by 
the NCI program staff shortly after the U01 awards are made and the NIH 
intramural projects are selected.  At this planning meeting, a Chair will be 
selected and the Group may:
-draft a charter to detail policies and procedures and agree on terms of the 
charter
-set a plan for location and time of future meetings
-review criteria for validation of a molecular target as a site of 
vulnerability for drug discovery
 
At subsequent meetings the Group will evaluate molecular target data presented 
by individual PI s.  As a Group they will determine the status of various 
target projects and facilitate the research efforts for target validation and 
drug discovery for each project presented.  

The  Molecular Target Analysis Group may establish subcommittees, as it deems 
appropriate, NCI staff may serve on subcommittees. 

In summary, the purpose of the Molecular Target Analysis Group is to apply its 
collective knowledge to accelerate the pace of identification of new molecular 
targets for drug discovery.  Members of the  Molecular Target Analysis Group 
and their collaborators will participate in recommending guidelines and 
standards for the discovery and validation of new targets, and will have the 
advantage of access to resources, information, technologies, ideas, and 
expertise to facilitate their research.  As targets are developed and 
validated, the NCI will provide a mechanism to disseminate information to the 
research community, with appropriate safeguards for protection of intellectual 
property.  The ideal outcome from these efforts would be the discovery of a 
new generation of agents useful for the treatment and/or prevention of cancer.  

The NCI will have the option to cross-file or independently file an 
application for investigational clinical trial (e.g., and Investigational New 
Drug Application [INDA] to the United States Food and Drug Administration) of 
any invention resulting from these NCI supported cooperative agreements.  
Reports of data required for inclusion in INDAs and Clinical Brochures and for 
cross-filing purposes shall be submitted promptly by the PI to an NCI Program 
Scientist upon request.  Such reports shall include background information, 
methods, results, and conclusions.  They will be subject to approval and 
revision by NCI and may be augmented with test results from other government-
sponsored projects prior to submission to the appropriate regulatory agency.

E. Arbitration Panel

Any disagreement that may arise on scientific/programmatic issues (within the 
scope of the U01 award or NIH intramural project), between the awardees and 
the NCI Extramural Program staff may be brought to arbitration.  An 
arbitration panel will be composed of three members: one selected by the 
Molecular Target Analysis Group, or by the U01 awardee or NIH intramural 
project in the event of an individual disagreement, a second member selected 
by the NCI, and third member agreed upon by the other two.  For U01 awardees, 
this special arbitration procedure in no way affects the awardee’s right to 
appeal an adverse action that is otherwise appealable in accordance with the 
PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 
16.

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.  

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 (by mail, FAX or e-mail) 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 RFA 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 the program staff listed under INQUIRES 
by the letter of intent receipt date listed in the heading of this RFA.
 
APPLICATION PROCEDURES

Applicants for either U01 awards or NIH Intramural projects must use the 
research grant application form PHS 398 (rev. 4/98).  Alternatively, NIH 
intramural project applicants must follow the directions in   Additional 
Instructions for NIH Intramural Project Applicants" below.  Application kits 
are available at most institutional offices of sponsored research and may be 
obtained from the Division of Extramural Outreach and Information Resources, 
National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910,  telephone 301/710-0267, 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).

SPECIAL INSTRUCTIONS FOR ALL APPLICANTS

1. Specific issues related to cooperative agreements must be addressed as 
follows.

o  Applicants must budget (i.e., based on a city centrally located in the USA) 
for travel and per diem expenses for Molecular Target Analysis Group meetings.  
In the first year, applicants should plan for two investigators, the principal 
investigator and an additional senior investigator, to attend two  Molecular 
Target Analysis Group meetings.  In the second and subsequent years, 
applicants should plan for the PI to attend two  Molecular Target Analysis 
Group meetings per year.

o  Applicants must include their specific plans for responding to the "Terms 
and Conditions of Award" section.  Applicants should state their willingness 
to collaborate and share data freely with the other MTDD awardees, to 
participate in planning and to serve on the Molecular Target Analysis Group 
and be bound by its decisions for setting the standards for characterization 
and validation, and to be able and willing to share data and communicate with 
each other and the NCI in an Internet environment.  Applicants should also 
describe how they will comply with the involvement of an NCI Program 
Scientist.

2.  Additional Materials to Include in the Application

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Failure to use 
this label could result in delayed processing of the application such that it 
may not reach the review committee in time for review.  In addition, the RFA 
title, MOLECULAR TARGET DRUG DISCOVERY FOR CANCER, and number, RFA CA-00-002, 
must be typed on line 2 of the face page of the application form and the YES 
box must be marked.

3.  Application Format to Follow

The format outlined in the form PHS 398 kit should be followed except for the 
additional materials listed below which should be included in the indicated 
order after the LITERATURE CITED section.
 
o  Acceptance of NCI Staff participation as described in  NCI Extramural Staff 
Responsibilities .

o  A statement by the PI accepting participation on the  Molecular Target 
Analysis Group and implementing, if applicable, the goals, procedures and 
policies agreed upon by the  Molecular Target Analysis Group.

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

o  An assurance plan 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.

U01 applicants (NIH intramural project applicants must use the address in 
section 3,  Additional Instructions for NIH Intramural Project Applicants" 
below), should submit a typewritten, signed original of the application, 
including the checklist, and three signed photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional signed photocopies of the 
application must also be sent 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 a U01 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 U01 application in 
response to this RFA 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 301/710-0267, 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.  The RFA label must 
be affixed to the bottom of the Face Page, as described above in section 2.

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 RFA, 
and for complying with the policies of the Molecular Target Analysis Group.  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 $300,000 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 
responsiveness by NCI.  Incomplete and/or non-responsive applications will be 
returned to the applicant without further consideration.  

Applications that are complete and responsive to the RFA 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 RFA are the discovery and 
validation of new molecular targets with the potential for developing assays 
for the discovery of new agents to treat or prevent cancer.  At minimum, a 
target should be identified (de novo, or from the literature), a validation 
plan outlined, and a conception of how the validated target can be developed 
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 RFA: 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. 

SCHEDULE

Letter of Intent Receipt Date:		June 6, 2000
Application Receipt Date:			July 18, 2000
Review by NCAB Advisory Board:		February 2001
Earliest Anticipated Start Date:		April 1, 2001

INQUIRIES
 
Written and telephone inquiries concerning this RFA are encouraged.  The 
opportunity to clarify  any issues or questions from potential applicants is 
welcome.
 
Direct inquiries regarding programmatic issues in cancer treatment, inquiries 
regarding access to the Natural Products Repository and inquiries regarding 
access to the Synthetic Compound Repository of NCI 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")

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 
6116 Executive Blvd., Room 8062, MSC 8239
National Cancer Institute 
Bethesda MD 20892-8239
Rockville, MD 20852 (express courier)
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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