Full Text CA-97-006
NIH GUIDE, Volume 26, Number 15, May 9, 1997
RFA:  CA-97-006
P.T. 34

  Chemistry, Organic 
  Medicinal Chemistry 
  Chemotherapeutic Agents 
  Drug Design 

National Cancer Institute
Letter of Intent Receipt Date:  June 20, 1997
Application Receipt Date:  August 22, 1997
The Developmental Therapeutics Program (DTP), Division of Cancer
Treatment, Diagnosis and Centers (DCTDC), National Cancer Institute
(NCI) invites Program Project grant applications (P01s) proposing
innovative combinatorial approaches to the generation of structural
diversity and smart assay development for cancer drug discovery
(Nature, Supplement to Volume 384, Issue No. 6604, November 7, 1996).
Applications responsive to this RFA will bring together 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 multidisciplinary teams for the
discovery of new agents that will 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 will include
the application of synthetic combinatorial or biosynthetic 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.
Structures based on clinically-approved anticancer drugs will not be
considered responsive to the RFA.
Although it is recognized that drug discovery can be a long and
arduous process involving many steps, including lead discovery, lead
optimization, and evaluation of promising candidates in pharmacology,
toxicology, formulation and other studies in an effort to identify
the most promising candidates for development to clinical trial, NCI
is prepared to assist any awardee in bringing promising therapeutic
candidates to clinical trial through its Decision Network process
(Edward A. Sausville, "Working with the National Cancer Institute",
Anticancer Drug Development Guide: Practical Screening, Clinical
Trial, and Approval edited by B. Teicher, Humana Press Inc., Totowa,
NJ, 1997 - in press) (available from Dr. Wolpert listed under
INQUIRIES).  Industrial partners also may be interested in supporting
developmental activities.  The goal of this RFA is to identify and
optimize lead structures.  Drug development activities, such as
large-scale production of an agent, are beyond the scope of the RFA.
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 Request
for Applications (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).
Applications may be submitted by domestic, for-profit, and nonprofit
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.  Applications may include participants from the same or
different departments in the same institutions, or from different
institutions, or from academic departments and industry.
Racial/ethnic minority individuals, women and persons with
disabilities are encouraged to apply as Principal Investigators
Support for this program will be through the National Institutes of
Health (NIH) program project grant (P01) mechanism.  The applications
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 also 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
This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-
initiated applications and will be reviewed according 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.
The NCI has set aside $3.75 million total costs (direct plus
facilities and administrative costs) for the first year of funding.
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.  Applicants may request up to $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. Budget requests
should be carefully justified and commensurate with the needs of the
project. Because the nature and scope of the research proposed in
response to this RFA may vary, it is anticipated that the size of the
awards may vary.  It is anticipated that four to five awards will be
made for periods up to five years, with the earliest expected award
date being April 1, 1998.
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.
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
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.
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 utilizing one well-defined reaction partner of
each type per reaction, mixtures of several known reaction partners
are utilized 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
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- -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.  Applications which define
and manipulate biosynthetic pathways but do not address the
generation of chemical diversity will not be considered responsive to
this RFA.
Novel Screening Approaches: "Smart" assays 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, assays of interest to promote 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 to be a basis for detection would all examples
clearly responsive to the RFA.
This initiative invites grant applications to support 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.
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.
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
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 reprinted
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.
Prospective applicants are asked to submit, by June 20, 1997, 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.  Applicants requesting budgets
greater than $500,000 total costs in any year of their proposed
application are required to contact NCI program staff prior to
submitting their applications (NIH GUIDE, Volume 25, Number 14, May
3, 1996).  Applications with budgets of more than $500,000 received
without prior communication with at least one of the NCI program
staff listed under INQUIRIES will not be accepted for review.
The letter of intent should be sent to the Referral Officer, National
Cancer Institute at the address listed under APPLICATION PROCEDURES.
Applications are to be submitted on the research grant application
form PHS 398 (revised 5/95) in conformance with the P01 application
guidelines of the NCI (revised 1995), which are available from the
NCI Referral Officer, Division of Extramural Activities, National
Cancer Institute Executive Plaza North, Room 636A, 6130 EXECUTIVE
BLVD MSC 7405, BETHESDA, MD 20892 (Telephone: 301-496-3428, FAX:
301-402-0275, Email:  FRIEDBET@DEA.NCI.NIH.GOV).  PHS 398 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@odrockm1.od.nih.gov.
The RFA label available in the PHS 398 (revised 5/95) application
form must be affixed to the bottom of the face page of the
application such that it may not reach the review committee in time
for review.  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 title and number of
the RFA 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:
BETHESDA, MD 20892-7710
NORTH BETHESDA, MD 20817 (for express/courier service)
In addition, at the time of submission,  send two complete copies
under separate cover to:
BETHESDA, MD 20892-7405 (or ROCKVILLE, MD 20852 for overnight mail
Telephone: 301-496-3428
FAX: 301-402-0275
The deadline for submission of applications will be August 22, 1997.
Late applications will not be accepted.  If an application is
received after the due date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG 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.
Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants and responsiveness by the NCI. Incomplete
applications will be returned to the applicant without further
consideration.  If NCI staff find that the application is not
responsive to the RFA, it will be returned to the PI without further
consideration.  The PI may submit the application as an unsolicited,
investigator-initiated P01 at the next deadline for competing P01
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 Review Logistics Branch of the Division
of Extramural Activities of NCI.  As part of the initial merit
review, all applicants will receive a written critique and may
undergo a process in which only those applications deemed to have the
highest scientific merit will be discussed, assigned a priority
score, and receive a second level of review by the National Cancer
Advisory Board.
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.
The initial review group will also examine the provisions for the
protection of human and animal subjects, if any, and the safety of
the research environment.
In addition to the standard Review Criteria used to evaluate P01
applications (as described in the  P01 Guidelines), the following
Review Criteria will be used to assess the scientific merit of each
o  scientific and technical merit and originality of the proposed
research plans;
o appropriateness and adequacy of the experimental approach,
including the design strategies for combinatorial synthesis or
biosynthesis of new leads; novelty and suitability of screens for the
discovery of lead structures; optimization strategy;
o  relevance of screens to the neoplastic process;
o  decision-making process in identifying leads for optimization;
o  plans for data storage and manipulation;
o evidence of research plans encompassing inter-disciplinary
collaboration and coordination addressing the goals of generation of
novel structures not based on clinically-approved anti-cancer drugs,
the screening of novel structures against defined biological or
biochemical target(s), and the optimization of lead structures;
o  adequacy of the scientific disciplines and specific competencies
represented by the Principal Investigator and Project Leaders;
research experience, competence, commitment, and time availability of
Principal Investigator, Project Leaders, and other key personnel;
o  leadership, scientific ability, and administrative experience and
competence of the Principal Investigator in the development,
implementation, and management of comprehensive, inter-disciplinary
research programs;
o adequacy of plans for effective team communication and
o evidence of the approval and commitment of institutions represented
by team members to project goals, and the availability and adequacy
of the existing physical facilities and resources necessary to
perform the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
The earliest date of award is April 1, 1998. 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.
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
Gordon M. Cragg, Ph.D.
Natural Products Branch, Developmental Therapeutics Program
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute-FCRDC
Fairview Center, Suite 206
P.O. Box B
Frederick, MD  21702-1201
Telephone:  (301) 846-5387
FAX: (301) 846-6178
Email:  cragg@dtpax2.ncifcrf.gov
Chemistry Issues
Ven Narayanan, Ph.D.
Drug Synthesis and Chemistry Branch
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 831
6130 Executive Boulevard, MSC 7448
Bethesda, MD  20892-7448
Telephone:  (301) 496-8795
FAX:  (301) 480-4817
Email: narayananv@dtpepn.nci.nih.gov
Screening Issues
George S. Johnson, Ph.D.
Grants and Contracts Operations Branch
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 841
6130 Executive Boulevard, MSC 7456
Bethesda, MD 20892-7456
Telephone: (301)-496-8783
FAX: (301)-402-5200
Email: johnsong@dtpepn.nci.nih.gov
Program Issues
Mary K. Wolpert, Ph.D.
Grants and Contracts Operations Branch
Division of Cancer Treatment, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Room 841
6130 Executive Boulevard, MSC 7456
Bethesda, MD 20892-7456
Telephone: (301)-496-8783
FAX: (301)-402-5200
Email: wolpertm@dtpepn.nci.nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Cynthia W. Mead
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Boulevard, MSC 7150
Bethesda, MD 20892-7150
Telephone: (301) 496-7800, ext. 228
FAX: (301) 496-8601
Email: meadc@gab.nci.nih.gov
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.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.  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.

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