CANCER DRUG DISCOVERY:  DIVERSITY GENERATION AND SMART ASSAYS

Release Date:  April 3, 1998

RFA NUMBER:  CA-98-009

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  October 21, 1998
Application Receipt Date:  November 18, 1998

PURPOSE

The Developmental Therapeutics Program (DTP), Division of Cancer Treatment and
Diagnosis (DCTD), National Cancer Institute (NCI) invites Program Project grant
applications (P01s) proposing a) innovative approaches to the generation of
structural diversity, such as combinatorial synthesis, parallel synthesis or
genetic manipulation of biosynthetic pathways in producer organisms and b) smart
assay development for cancer drug discovery (Nature, Supplement to Volume 384,
Issue No. 6604, November 7, 1996). Applications responsive to this Request for
Applications (RFA) will bring together multidisciplinary teams of chemists and
biologists who will propose novel approaches to the discovery of compound classes
potentially active against cancer.  This initiative seeks to catalyze the
formation of such teams to exploit opportunities presented by the rapidly
advancing state of contemporary chemistry and biology.  Participants may come
from the same or different departments in the same academic institution, or from
different institutions, or from (an) academic department(s) and industry. 
Approaches may include the application of synthetic or biosynthetic combinatorial
approaches to generate libraries of novel structures.  Conceivably both
techniques might be utilized by different components of the same research group,
and active products of the biosynthetic approach may serve as novel scaffolds for
elaboration using combinatorial synthetic technology.  In close association with
the generation of compound libraries, applicants should also propose the
development or application of novel assays directed at molecular events or
targets important in the neoplastic process and suitable for assaying the
compound libraries.  Applicants may employ any biological system that is likely
to be informative in the context of this initiative.  Reliance solely on anti-
proliferative or cytotoxic assays which do not provide information on
vulnerabilities of selected targets will not be responsive to this RFA. 
Manipulation of structures based on clinically-approved anticancer drugs also
will not be considered responsive to the RFA.

A former RFA with the same title (CA-97-006) was published on May 9, 1997 in the
NIH Guide for Grants and Contracts, and several awards are being negotiated as
a result of that competition.  Because of the promise of the new approaches
described above for drug discovery and the rapidly changing and improving
technology in creating new molecules and novel assays, this effort is being
recompeted.  A reissuance will encourage the formation of new groups, especially
those in the emerging area of biosynthesis, and will allow the previously
unsuccessful groups another opportunity to compete.

Although it is recognized that the discovery and development of effective
therapies can be a long and arduous process involving many steps, including lead
discovery and optimization and evaluation of the most promising materials in
pharmacology, toxicology, formulation and other studies to identify candidates
for clinical development,  NCI is prepared to assist any awardee in bringing new
products to clinical trial and has developed processes, such as the Decision
Network process, to expedite the translation of laboratory discoveries to
clinical evaluation (Edward A. Sausville, "Working with the National Cancer
Institute", Anticancer Drug Development Guide: Practical Screening, Clinical
Trials, and Approval edited by B. Teicher, Humana Press Inc., Totowa, NJ, 1997,
pp. 217-226) (available from Dr. Wolpert listed under INQUIRIES).  Industrial
partners also may be interested in supporting developmental activities, such as
large-scale production, which are beyond the scope of the RFA. The goal of this
RFA is to identify and optimize lead structures.

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, Cancer Drug Discovery: Diversity
Generation and Smart Assays, is related to the priority area of cancer. 
Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: 
Stock No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone 202-512-1800).

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 not be submitted by foreign institutions;
however, an application from a domestic institution may include foreign
components as research projects or core activities, as defined below under
MECHANISM OF SUPPORT.  Racial/ethnic minority individuals, women and persons with
disabilities are encouraged to apply as Principal Investigators (PIs).

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) program project grant
(P01) mechanism.  Responsibility for the planning, direction, and execution of
the proposed project will be solely that of the applicant.  The total project
period for an application submitted in response to the RFA may not exceed five
years.  The earliest expected award date is April 1999.  Because the nature and
scope of the research proposed in response to the RFA may vary, it is anticipated
that the size of individual awards will vary.

An application should be constructed using the P01 application guidelines of the
NCI, which are available from the NCI Referral Officer as described below under
APPLICATION PROCEDURES.  The P01 mechanism is designed to support multiple,
interacting projects focused on a central theme.  P01s must have a minimum of
three projects and may include cores.  A core is a separately budgeted component
of a P01 that provides essential facilities or services to two or more of the
proposed research projects.  A core may not count as one of the three research
projects.  Cost sharing arrangements with industry are encouraged, but detailed
project descriptions must be provided even if no funds are requested for a
project or core activity.  P01s may support projects that are performed at
multiple sites but coordinated by a single Principal Investigator at the grantee
institution.  PIs will be responsible for the planning, direction and execution
of the proposed project.  An award will be made only to the PI's institution. 
All activities will be coordinated through an administrative core located at the
PI's institution.  An administrative core is recommended, especially if multiple
institutions are involved in the P01.

This RFA is a one-time solicitation.  Future unsolicited continuation
applications will compete with all investigator-initiated applications and will
be reviewed according to the customary peer review procedures.

Except as otherwise stated in the RFA, awards will be administered under PHS
grants policy as stated in the Public Health Service Grants Policy Statement,
DHHS Publications No. (OASH) 90-50-000, revised April 1, 1994.

FUNDS AVAILABLE

The NCI has set aside $3.00 million total costs (direct plus facilities and
administrative costs) for the first year of funding, and the anticipated number
of new awards is expected to be at least three. The number of awards and level
of support is dependent on the receipt of a sufficient number and diversity of
applications with high scientific merit.  It is expected that most awards will
not exceed $950,000 total costs (direct plus facilities and administrative costs)
for year one with no more than a 3% per year increase for future years. 
Exceptionally meritorious applications may be funded at a higher level provided
the budget is adequately justified and considered reasonable by peer review. 
Budget requests should be carefully justified and commensurate with the needs of
the project.

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.

RESEARCH OBJECTIVES

Background

Recent developments in chemistry and biology suggest possibilities for an
entirely new vision for cancer drug discovery.  The unprecedented power of
chemical and biological combinatorial techniques have made it possible to
generate impressive structural variation in the laboratory.  At the same time the
fast-paced identification of gene products, gene sequences, and pathways relevant
to neoplasia enables the creation of novel assays for biological functions
relevant to cancer.  These should permit a much more informative exploration of
"diversity space" than has been possible previously for biological activities
with therapeutic implications.  Implementation of such assays on a large scale
is now much more practical by remarkable engineering advances in robotics,
miniaturization, and information processing.  NCI proposes the present initiative
to create multidisciplinary teams for drug discovery featuring close
collaboration between chemists and biologists to explore novel approaches that
will take full advantage of the opportunities presented by scientific advances.

For many years, there have been extensive programs for the acquisition of novel
structures from both natural and synthetic sources and for testing extracts and
compounds in in vivo and in vitro screens for antiproliferative activity.  This
approach has been productive and has, in fact, yielded most of the agents in the
current armamentarium (platinum complexes, nucleoside analogs, antifolates, vinca
alkaloids, taxanes and camptothecin derivatives).  The current state of the
relevant science and technology suggests now, however, that a very different
paradigm for the discovery of anticancer agents might be at hand.  It seems
clear, for example, that a vast diversity of chemical structures can be generated
in the laboratory over surprisingly short time frames.  There is no consensus at
present that the degree of diversity derivable from laboratory experiments yet
approximates what can be found in nature, but experience to date suggests that
many millions of distinct structures can result from synthetic efforts extending
over only a few months.  In a similarly revolutionary vein, assays for biological
relevance can now be designed to give information not only about phenotypic
alteration, such as growth arrest or cell death, but about the effect on
particular molecular targets of pathways known or suspected to have biological
relevance to cancer.

Research Goals and Scope

Since a multidisciplinary collaboration is envisioned, successful applicants must
present plans for effective team communication and coordination of effort
covering development, implementation, and conduct of all aspects of the research
program from generation of novel structures and screening data to data management
and decision-making.  Although it is desirable that team members can demonstrate
evidence of previous collaborations with one another, previous collaborations are
not a requirement of the RFA.

Structural diversity may be generated by a variety of approaches, including
combinatorial or parallel synthesis, or by genetic manipulation of biosynthetic
pathways in producer organisms.  The molecules produced may represent de novo
collections of novel structures, or efforts to optimize lead structures with
promising but incompletely developed potential.  In no case should the compounds
to be studied represent iterations of structures already FDA-approved for use in
the treatment of human malignancy.  An applicant may propose the generation of
various types of structures, such as low molecular weight organic molecules or
larger products, such as peptides, based on any reasonable hypothesis for the
generation of novel anticancer agents.  Although the focus of this RFA is on
generating and optimizing lead structures useful for the treatment of cancer,
other factors, such as drug delivery to the target site and ease of production,
will determine the ultimate success of a product.

Combinatorial Organic Synthesis: A key feature of combinatorial techniques is
that compound synthesis can be designed such that a range of structures can be
produced simultaneously as mixtures in the same reaction vessel or individually
in parallel using semi-automated synthesis.  The repetitive nature of the
synthetic processes involved in most combinatorial applications lends itself to
automation or semi-automation.  This key feature means that the bench chemist can
singlehandedly prepare tens, hundreds, or thousands of compounds of known
structures in the time that it would take to prepare only a few pure entities by
orthodox methodology.

Combinatorial technology can be practiced in either a solution or solid-phase
format.  Solution techniques utilize methods essentially similar to standard
methods for the synthesis of single compounds, except that instead of using one
well-defined reaction partner of each type per reaction, mixtures of several
known reaction partners are added as building blocks, thus resulting in mixtures
of analogs.  The type of the chosen chemical reaction and the number of reactants
depend on the nature of the desired structures.  These mixtures may not be
purified elaborately but are directly subjected to screening against the desired
target (e.g., receptor, enzyme, antibody, cell).  The chemistry is then repeated
a few times in batches using different but well defined mixtures of reaction
partners, and the products isolated and screened.  In order to identify the
leads, the chemistry is repeated several times using fewer reaction partners in
each run, and the products are screened.  This deconvolution process is repeated
until the most potent lead is identified.

In solid-phase approaches, pin or bead techniques permit the synthesis of
different molecules on each pin (i.e., "one molecule-one bead").  The products
of solid-phase synthesis can be cleaved from the backbone matrix for solution
screening (which is essential when the screening target is a cell), or the most
active molecules displayed on the polymer surface may be detected using molecular
targets (receptor, enzyme, antibody) pre-tagged with a means of detection
(visible color, fluorescence, radioactivity, chromophore, etc.) and then isolated
and identified.

Manipulation of Biosynthetic Pathways: Biosynthetic approaches to generating
diversity may also be used to produce large numbers of novel structures.  Recent
progress has focused on the creation of hybrid antibiotics through genetic
engineering (Katz et al., Ann. Rev. Microbiol 47: 875-912, 1993) and in the
production of novel structures based on genetic manipulation of the aromatic
polyketide biosynthesis pathways in prokaryotic microorganisms (Khosla et al.,
Nature 375: 549-554, 1995). A set of programming rules, which helps to predict
the potential structures of novel polyketides produced by strains carrying these
recombinants, has begun to emerge and forms the basis for the use of biosynthesis
as a route to new aromatic polyketides.  Polyketides are described in
biosynthetic rather than structural terms.  Broadly, this category comprises
structures derived wholly or partly from poly-þ-ketomethylene chains, and
includes a rich source of bioactive molecules, including antibiotics, such as the
tetracyclines, anticancer agents, such as daunomycin, and immunosuppressants,
such as FK506 and rapamycin.  Outside the polyketide area there is still much to
be learned in elucidating the biosynthetic pathways of secondary metabolites from
other microbes, plants, or marine organisms.  The exploration of biosynthetic
pathways in plants and marine organisms has been much more difficult than that
of their prokaryotic counterparts because of slower growth rates, the often more
complicated structures of the secondary metabolites, the existence of multi-gene
pathways that are not clustered in the genome, and the presence of enzyme-
inactivating constituents.  Definition of the pathways involved in the production
of non-polyketide-derived structures especially by employing cell culture and
modern molecular biologic techniques may also be tied to the generation of
structural diversity.  Recombinant technology has paved the way for
characterizing the genomic information of new species and strains of
microorganisms which were deemed "unculturable" previously and has opened a huge
resource for chemical diversity. Applications which define and manipulate
biosynthetic pathways but do not address the generation of chemical diversity
will not be considered responsive to this RFA.  Although it is recognized that
biosynthetic approaches may not generate the volume of compounds possible with
synthetic approaches, nature has produced many interesting "scaffolds" and the
percentage of biologically active materials may be higher.  Applications which
propose a combination of combinatorial biosynthetic and synthetic  approaches are
especially encouraged.

Novel Screening Approaches: A "smart" assay may be operationally defined as a
screening system that by its very operation conveys information about new
chemistry or biology of "hits" in the system.  For example, an assay tailored to
produce a specific readout regarding downregulation of the RAS signaling pathway
could be considered "smart".  A variety of intervention points in a pathway may
regulate a disease process.  Assays of interest may couple the use of a cloned
and expressed target protein or a nucleic acid sequence in tandem with a chemical
or biosynthetic process that generates molecules for further study. 
Alternatively, the use of genetically definable yet underexplored organisms such
as yeast, Drosophila, or C. elegans, production of expression vectors that may
operate only in the presence of a compound with the desired properties,
development of detection techniques based on novel patterns of molecular
recognition, or strategies that require the operation of a particular molecular
target as a basis for detection would all be examples clearly responsive to the
RFA.  In vivo studies are not required in this initiative; however, limited
"proof of concept" experiments may be proposed and are encouraged depending on
the needs of the project.  Expensive toxicology tests, such as those required for
the submission of Investigational New Drug Applications to the Food and Drug
Administration, are beyond the scope of the RFA.  Applicants may propose existing
assays, new assays, or a combination of both types. However, rather than merely
proposing a collection of assays, applicants should endeavor to propose assays
that fit a theme and test a hypothesis with relevance to cancer.

SPECIAL REQUIREMENTS

This initiative requires the assembly of inter-disciplinary teams with the skills
needed to pursue successfully the generation of novel structures, their screening
against defined biological or biochemical target(s), and the optimization of lead
structures.  Since the team may include investigators from more than one
institution, "letters of intent to collaborate with the applicant organization"
signed by the appropriate institutional official from each participating
organization must be included in the application.  Submission of formal
collaborative documents can be delayed until time of award.

The NCI recognizes that source countries retain interests in samples collected
in their domains. All applicants who propose to use organisms or other naturally-
derived materials of foreign origin in their studies must provide a plan, signed
by representatives of all participating institutions, for equitable return of a
portion of any profits or royalties, or other acceptable forms of compensation,
derived from their discoveries to indigenous peoples, research collaborators,
cooperating institutions or Governmental entities in the countries of origin, as
appropriate to their contributions.  It is preferred that this plan be submitted
with the application.  If this plan is not included as part of the application,
it must be submitted as a condition for award to a Program Official to be
designated at the time of award.

Since the discovery of new anticancer agents may result from these P01 projects,
it is essential that applicants provide plans to assure patent coverage.  The
situation could be complicated since multiple institutions, including industry,
may be involved.  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.

NOTE: A formal statement of Patent Agreement among participants and their
institutions, 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 patent arrangements for each
participant and participating institution is preferred with the application.  If
this signed agreement is not included in the application, it must be submitted
as a condition for award to a Program Official to be designated at the time of
award.

Applicants should plan to attend an annual meeting of awardees of this and the
previous RFA with the same title to share research findings and to discuss issues
of common interest or concern.  For budgetary purposes, applicants should budget
for two representatives of their P01 to attend an annual meeting at the NIH
campus in Bethesda, MD.

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.

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.

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.

NIH POLICY AND GUIDELINES ON THE 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 NIH,
unless there are scientific and ethical reasons not to include them.  This policy
applies to all applications submitted in response to this RFA.  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

LETTER OF INTENT

Prospective applicants are asked to submit, by October 21, 1998, a letter of
intent that includes a descriptive title of the proposed research and a list of
titles for the anticipated components of the P01, the name, address, and
telephone number of the Principal Investigator, the identities of other key
personnel and participating institutions, and the 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 a
subsequent application, the information that it contains allows NCI staff to
estimate the potential review workload and avoid conflict of interest in the
review.

The letter of intent is to be sent to Ms. Toby Friedberg at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application form PHS 398
(rev. 5/95).  Application kits are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email:
ASKNIH@od.nih.gov.

Applications must conform the guidelines contained in the P01 application
guidelines of the NCI (rev 03/97), which are available via the World Wide Web at
http://deainfo.nci.nih.gov/ following the path Extramural Activities, to Grant
Guidelines and Descriptions, to Research Program Projects and Centers; P-series,
to P01 Guidelines.  Guidelines are also available from Ms. Toby Friedberg at the
address listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 5/95) 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 and
number must be typed on line 2 of the face page of the application and the YES
box must be marked.

Submit a signed, typewritten 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  20817-7710 (for express/courier service)

At the time of submission, two additional copies of the application must be sent
to Ms. Toby Friedberg at the address listed under INQUIRIES.

Applications must be received by November 18, 1998.  Applications received after
that date will be returned to the applicant without review.  The Center for
Scientific Review (CSR) will not accept any application in response to the RFA
that is essentially the same as one currently pending initial review unless the
applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does not
preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by the NCI.  Incomplete and/or non-responsive applications will
be returned to the applicant without further consideration.  The PI may choose
to submit the application as an unsolicited, investigator-initiated P01 at the
next deadline for competing P01 applications.

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 Special Review, Referral and Resources Branch (SRRRB), Division of Extramural
Activities, NCI.  As part of the initial merit review, a process may be used by
the initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit relative to other
applications received in response to the RFA.  Applications judged to be
competitive will be discussed and be assigned a priority score.  Applications
determined to be non-competitive will be withdrawn from further consideration and
the Principal Investigator and the official signing for the applicant
organization will be notified.

Because of the time allotted for the review, no site visits are planned. 
Therefore, it is important that all information necessary for an informed review
be included in the written application by the due date.  The Scientific Review
Administrator (SRA) will contact the PI for the opportunity to provide
supplementary material, such as recent publications, before the review.  No
material should be submitted unsolicited.

Review Criteria

The five criteria to be used in the evaluation of grant applications are listed
below.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.  Note that the
application does not need to be strong in all categories to be judged likely to
have a major scientific impact and thus deserve a high priority score.  For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

1.  Significance.  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

2.  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?  Are the screens relevant to the neoplastic process?  Is the
decision-making process adequate for identifying and optimizing leads?  Are the
plans for data storage and manipulation adequate?  Are the plans for
multidisciplinary collaboration and coordination adequate?

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?

4.  Investigator.  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

5.  Environment.  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups 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 for the protection of
human and animal subjects; and the safety of the research environment.

Review criteria used to evaluate P01 applications will also be used in the review
of these applications.  Peer review of the overall scientific and technical merit
emphasizes a synthesis of two major aspects: 1) review of the P01 as an
integrated effort focused on a central theme and 2) review of the merit of
individual research projects and core components in the context of the proposed
P01.  Applicants are encouraged to study the evaluation criteria cited in the P01
guidelines (referred to in  APPLICATION PROCEDURES) before preparing their
applications.  The following sections from the P01 guidelines will apply to the
review of this RFA: REVIEW CRITERIA FOR THE OVERALL PROGRAM, REVIEW CRITERIA FOR
THE PROGRAM AS AN INTEGRATED EFFORT, REVIEW CRITERIA FOR PROJECTS, REVIEW
CRITERIA FOR CORE(S) (if applicable), and ADDITIONAL CRITERION FOR AMENDED
APPLICATIONS (if applicable).

AWARD CRITERIA

The earliest date of award is July 1, 1999. The following will be considered in
making funding decisions:

o  Scientific merit as determined by peer review
o  Diversity of applications and programmatic priorities
o  Availability of funds
o  Responsiveness to the goals and objectives of the RFA.

Schedule

Letter of Intent Receipt Date:   October 21, 1998
Application Receipt Date:        November 18, 1998
National Cancer Advisory Board:  June 1999
Anticipated Award Date:          July 1, 1999

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Biosynthetic Issues

Yali Hallock, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841, MSC 7456
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email:  yh11c@nih.gov

Chemistry Issues

John A. Beisler, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841, MSC 7456
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email:  beislerj@dtpepn.nci.nih.gov

Screening Issues and Scope of Studies

Mary K. Wolpert, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 841, MSC 7456
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email:  wolpertm@dtpepn.nci.nih.gov

Direct inquiries regarding review issues, requests for the NCI P01 Guidelines,
and address the letter of intent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC 7407
Bethesda, MD  20892-7407
Rockville, MD  20852-7407 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  FRIEDBET@DEA.NCI.NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Cynthia W. Mead
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 254
FAX:  (301) 496-8601
Email:  meadc@gab.nci.nih.gov

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 the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by
Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies
and Federal Regulations 42 CFR Parts 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 Public Health Service (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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