NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY

Release Date:  November 25, 1998

PA NUMBER:  PAR-99-019

P.T.

National Cancer Institute

Letter of Intent Receipt Dates:  January 15, 1999 and September 15, 1999
Application Receipt Dates:  February 19, 1999 and October 19, 1999

PURPOSE

This Program Announcement (PA) encourages the use of non-mammalian organisms to
discover new cancer therapies.  The goal is to identify key genes, enzymatic
activities, components of signaling pathways, or cellular processes, which are
altered in human cancer, as potential intervention points or targets that could
be used in the design of new cancer drugs.  Projects could focus on validating
inferences already drawn from comparative study of cancerous and normal cells,
exploring promising leads from the nature of mutations known to be associated
with cancer development, or testing hypotheses generated by the identification
of new and unknown gene products, such as those sequenced through the NCI's
Cancer Genome Anatomy Project (CGAP).  For example, projects may include 
development of organisms in which genes in key pathways or processes are mutated 
or in which human transgenes are expressed to simulate changes known to occur 
in human cancers.  These genetic manipulations could present a "proof of principle" 
or validation of the importance of the target genes to the development of cancer.  
Some examples of genes that are well studied in model organisms and known or 
strongly suspected of involvement in cancer include oncogenes, proto-oncogenes, 
some cell cycle and signal transduction genes, and DNA repair genes.

The use of multiple grant funding mechanisms allows support for a broad range of
projects at various stages of development.  The exploratory/developmental R21
mechanism supports pilot projects or feasibility studies for new or
underdeveloped approaches.  Accordingly, a sound research plan, but preliminary
not data, are required. The R01 supports more advanced projects and also
collaborative research efforts between experts in non-mammalian biology and
investigators with experience in mammalian cancer models for comparative or proof
of principle, validation studies.

Small businesses are encouraged to consider a parallel program announcement of
identical scientific scope that utilizes the Small Business Innovation Research
(SBIR) and Small Business Technology Transfer (STTR) mechanisms (PAR-99-020). 
It should be noted that a search for small molecule inhibitors through screening
is appropriate for projects submitted for the SBIR program announcement.

Although this PA is being issued by NCI, the National Institute of General
Medical Sciences (NIGMS) has an interest in supporting projects related to this
topic.  Studies of growth regulation, cell cycle control, or other basic studies
that are not explicitly focused on tumor target cell systems may receive primary
assignment within the NIGMS or another institute.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Non-Mammalian Organisms as Models
for Anticancer Drug Discovery, 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 foreign and domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Research support mechanisms for this PA are the investigator-initiated research
project grant (R01) and the exploratory/developmental grant (R21).  R01 grants
provide support for up to five years.  R21 grants provide support for two years
with a budget of up to $100,000 direct costs for each year.  Collaborative
arrangements involving more than one institution are encouraged, including
participation of the pharmaceutical industry where appropriate.

Awards will be administered under NIH grant policy as stated in the NIH Grants
Policy Statement (rev. 10/98).

RESEARCH OBJECTIVES

The goal of cancer therapy is to eliminate malignant cells while sparing normal
cells.  Current clinically important drugs act as cytotoxic agents by binding to
or damaging DNA, altering cellular mechanisms, or binding to structural proteins
such as tubulin causing disruption of cell function.  Generally, they were
discovered as anti-proliferatives without specific consideration to site of
action.  Thus, as might be expected, they show significant toxicity to normal
cells which limits their clinical usefulness.  Targeting specific cell control
elements that are mutated in tumor cells provides a new and potentially valuable
approach to identify new, more selective, and less toxic agents for the cancer
armamentarium.

A vast array of mutated proteins, regulatory processes, and signaling pathways
has been implicated in cancer genesis and progression.  However, only a select
few, such as ras farnesylation and various protein tyrosine kinases, have been
approached for cancer drug discovery.  Determining which in this multitude of 
alterations and mutations are sites of vulnerability and are thus of importance
for intervention, as well as designing approaches to exploit these sites for
cancer drug discovery, are clearly daunting tasks.

Non-mammalian organisms offer an extraordinary opportunity to evaluate the
importance and vulnerability of these sites and to suggest which could be of 
importance for drug discovery.  Key regulatory pathways among eukaryotic
organisms demonstrate a striking similarity.  Importantly, cancer gene homologs
and functional pathways containing homologs are of importance in a wide variety
of cells including those of non-mammalian origin.  Although not always of
identical importance in humans, common pathways or at least portions of such
pathways could be considered to be "functional cassettes" performing similar
tasks within cells or organisms.  For this reason, non-mammalian organisms, which
are easier to manipulate genetically, have been valuable in defining new pathways
relevant to neoplasia as well as functional relationships among the various
pathways.  For example, at least 100 genes have been identified in yeast which
have been classified as "damage control elements" whose gene products are
involved in functions such as DNA repair, cell cycle regulation, check point
control, and spindle formation.  Several have been shown to have homologs in
human cells such as the MSH2 and MLH1 repair genes and the ATM (ataxia-
telangiectasia) cancer susceptibility gene.  Likewise, C. elegans biology has
defined several genes important to apoptotic pathways with clear homologs in
humans.  Drosophila have recently highlighted the importance of the sonic-
hedgehog pathway, whose members include a gene inactivated in basal cell
carcinoma.  Xenopus and zebrafish are additional non-mammalian organisms whose
biology is being actively studied and are known to contain homologs of cancer
relevant proteins.  Importantly, genomic sequences of non-mammalian organisms are
known as in the case of yeast or are being determined at a rapid pace, thus
providing a valuable asset for delineating the complexities of signaling pathways
and control functions.

LETTER OF INTENT

Prospective applicants are asked to submit, by the dates listed on the first page
of this PA, a letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone numbers of the Principal Investigator,
the identities of other key personnel and participating institutions, and the
number and title of the PA in response to which the application may be submitted. 
Although a letter of intent is not required, is not binding, and does not enter
into the review of 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 Dr. George S. Johnson at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted on the receipt dates listed on the first page of the
PA.  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, Email: grantsinfo@nih.gov.
The title and number of the program announcement must be typed in Section 2 on
the face page of the application.

The completed original application and three legible copies must be sent or
delivered to:

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

To ensure that the application is received in sufficient time for the review,
send two additional copies to:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6130 Executive Boulevard, Room 636a
Bethesda, MD  20892-7405
Rockville, MD  20852 (for express/courier service)
Telephone:  (301) 496-3428
FAX:  (301) 402-0275
Email:  friedbet@dea.nci.nih.gov

Applications must be received by the receipt dates listed on the first page of
this PA.  The Center for Scientific Review (CSR) will not accept any application
in response to this PA 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 a substantial revision of an
application already reviewed, but such application must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Applications assigned to NCI and considered responsive to the PA, will be
reviewed for scientific and technical merit by a special emphasis panel convened
by the Division of Extramural Activities, NCI, in accordance with the standard
NIH peer review procedures.  Applications that are complete but are judged to be
non-responsive to this PA will be assigned on the basis of established PHS
referral guidelines.  These applications will be evaluated for scientific and
technical merit by an appropriate review group convened in accordance with NIH
peer review procedures.  Following scientific-technical review, the applications
will receive a second-level review by the appropriate national advisory council.

Review Criteria

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?

3.  Innovation.  Does the project employ novel concepts, approaches or method? 
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?

6.  Preliminary data will not be required for R21 applications.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications. The following will be considered in making funding decisions: 
Quality of the proposed project as determined by peer review, availability of
funds, and program balance.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

George S. Johnson, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
Executive Plaza North, Room 841
Bethesda, MD  20892-7456
Telephone:  (301) 496-8783
FAX:  (301) 402-5200
Email: johnsong@exchange.nih.gov

Direct inquiries regarding fiscal matters to:

Theresa Mercogliano
National Cancer Institute
Executive Plaza South, Room 243
Bethesda, MD  20892
Telephone:  (301) 496-7800 ext. 243
FAX: (301) 496-8601
Email: theresa.mercogliano@nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636, MSC-7407
Bethesda, MD  20892
Rockville, MD  20852-7407 (for express/courier service)
Telephone: (301) 496-3428
FAX:  (301) 402-0275
Email:  friedbet@dea.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 52 and 45 CFR Part 74 and part 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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