NON-MAMMALIAN ORGANISMS AS MODELS FOR ANTICANCER DRUG DISCOVERY: SBIR/STTR
INITIATIVE

Release Date:  November 25, 1998

PA NUMBER:  PAR-99-020

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 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
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.

Investigations in response to this PA should provide insight into which genes or
gene products in cancer-relevant pathways are potential targets for human cancer
treatment.  Projects of a general nature not specifically related to new cancer
target or drug discovery will not be considered responsive.  A search for small
molecule inhibitors through screening is appropriate.

Although this PA is being issued by the 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 be assigned to
NIGMS or another Institute.

This PA must be read in conjunction with the OMNIBUS SOLICITATION OF THE PUBLIC
HEALTH SERVICE FOR SMALL BUSINESS INNOVATION RESEARCH GRANT (SBIR) APPLICATIONS
(PHS 98-2) and the OMNIBUS SOLICITATION OF THE NATIONAL INSTITUTES OF HEALTH FOR
SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) GRANT APPLICATIONS (PHS 98-3).  All of
the instructions within the omnibus solicitation apply with the following
exceptions:
-Special receipt dates
-Initial review convened by the NCI Division of Extramural Activities
-Additional 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 PA, "Non-Mammalian Organisms as Models
for Anticancer Drug Discovery: SBIR/STTR Initiative", 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

Eligibility requirements are described in the OMNIBUS SOLICITATIONS.  Any small
business concern, independently owned and operated by United States citizens or
lawfully admitted permanent resident aliens, which is located in the United
States and is organized for profit, may apply.

MECHANISM OF SUPPORT

Support for the PA is through the SBIR and STTR mechanisms which are set-aside
programs.

Applications can be submitted for support as Phase I STTR (R41) or Phase I SBIR
(R43) grants: Phase II STTR (R42) or Phase II SBIR (R44) grants; or under the
SBIR/STTR  FAST-TRACK option as described in the OMNIBUS SOLICITATIONS.  Phase
II applications in response to this PAR will only be accepted as competing
continuations of previously funded NIH Phase I SBIR/STTR awards.  The Phase II
proposal must be a logical extension of the Phase I research.

Information on the FAST-TRACK process and the OMNIBUS SOLICITATIONS are available
at: http://www.nih.gov/grants/funding/sbir.htm

Unless otherwise noted, all PHS grants policies apply.

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-proliferative agents 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 and more selective agents to add to 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 tyrosine protein 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 cells 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 growth 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 and in identifying interactions among components of pathways as well
as functional relationships among the 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-hedge hop 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 basis 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 number of the Principal Investigator,
the identities of other key personnel and participating institutions, and the
number and title of the PAR 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

OMNIBUS SOLICITATIONS for both the SBIR and STTR programs are available
electronically through the NIH, Office of Extramural Research "Small Business
Funding Opportunities" web site:  http://www.nih.gov/grants/funding/sbir.htm. 
Hard copies, subject to availability, may be obtained from the PHS SBIR/STTR
Solicitation Office, phone (301) 206-9385; FAX (301) 206-9722; email
a2y@cu.nih.gov.  Helpful information in preparation of the application can be
obtained: http://www.nih.gov/grants/funding/sbirsttradvice.htm

Applications in response to this PA are to be submitted on the grant application
form PHS 6246-1 (1/98) for SBIR Phase I
[http://www.nih.gov/grants/funding/sbir1/sbir.htm], PHS 6246-3 (1/98) for STTR
Phase I [https://grants.nih.gov/grants/funding/sbirsttr1/index.htm], PHS 6246-2 (1/98)
for SBIR Phase II [http://www.nih.gov/grants/funding/sbir2/index.htm], and PHS
6246-4 (1/98) for STTR Phase II
[http:/www.nih.gov/grants/funding/sttr2/index.html].

The applications are also located in the back pages of the OMNIBUS SOLICITATIONS. 
Applications will be accepted on February 19, 1999 and October 19, 1999.  The
title and number of this PA must be typed in line 2 on the face page of the
application.

Potential applicants are encouraged to contact program staff for guidance and to
read the advice and information on the web sites.  However, responsibility for
planning, direction, and execution of the proposed research will be solely that
of the applicant.

As stated in the MECHANISM OF SUPPORT section, applications may be submitted for
Phase I alone (R41/43), or Phase II (R42/44) alone if there has been previous and
successful Phase I support, or through the FAST TRACK mechanism. Application
instructions specified in the OMNIBUS SOLICITATIONS for each mechanism must be
followed.

The normal level of support and period of time for a Phase I SBIR award is
$100,000 and six months; for a Phase II SBIR award, $750,000 and two years.  The
normal level of support and period of time for a Phase I STTR award is $100,000
and one year; for a Phase II STTR award is $500,000 and two years.  However,
applicants may propose longer periods of time and greater amounts of funds if
necessary for completion of the project.  (See NIH Guide, February 12, 1998;
http://www.nih.gov/grants/guide/notice-files/not98-014.html).

Phase I, FAST TRACK applications must specify clear, measurable goals that should
be achieved prior to Phase II funding.  Failure to provide measurable goals and
sufficient detail in the Phase II application may be sufficient reason for the
peer review committee to exclude the Phase II application from consideration.

Phase II applications submitted in response to this PA will only be accepted as
continuations of previously funded Phase I grants.  The Phase II proposal must
be a logical extension of the Phase I research but not necessarily a Phase I
supported in response to this PA.

An additional requirement of the FAST TRACK mechanism is the commitment for funds
and/or resources for commercialization of the product.  The Commitment Appendix
to the Phase II application must specify amount of funds and/or nature of
resources that will be dedicated to activities directly related to the SBIR/STTR
project and must describe those activities.  If such commitment is from an 
investor or partner organization, a copy of the agreement or a letter describing
the details of the agreement must be provided.  The small business concern must
also submit a concise Product Development Plan (limited to five pages) as an
Appendix to the Phase II application addressing the four areas described in the
instructions for FAST TRACK applications in the OMNIBUS SOLICITATIONS.

The completed original application and one legible copy 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 expedite the review process, at the time of submission, send one additional
copy of the application 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

Applications must be received by the receipt dates listed at the top of the first
page of this PA.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the Center for Scientific Review
(CSR) for completeness and by the NCI for responsiveness. Applications not
adhering to application instructions described above and those applications that
are incomplete or non-responsive will be returned to the applicant without
review.

Applications will be reviewed for scientific and technical merit by an initial
review group convened by the NCI Division of Extramural Activities, in accordance
with the standard NIH peer review procedures. As part of the initial merit
review, all applications will receive a written critique and undergo a process
in which only t hose applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed assigned
a priority score, and receive a second level review by the National Cancer
Advisory Board.

Review Criteria

Review criteria are as described in the OMNIBUS SOLICITATIONS:

1.  The soundness and technical merit of the proposed approach.

2.  The qualifications of the proposed Principal Investigator, supporting staff,
and consultants.

3.  The scientific, technical, or technological innovation of the proposed
research.

4.  The potential of the proposed research for commercial application.

5.  The appropriateness of the budget requested.

6.  The adequacy and suitability of the facilities and research environment.

7.  Where appropriate, the adequacy of assurances detailing the proposed means
for (a) safeguarding human or animal subjects and/or (b) protecting against or
minimizing any adverse effect on the environment.

The Phase I application should specify clear, measurable goals (milestones) that
should be achieved prior to initiating Phase II. Failure to provide clear,
measurable goals may be sufficient reason for the study section to judge the
application non-competitive.

AWARD CRITERIA

Applications will compete for available funds with all other approved SBIR and
STTR applications.  Funding decisions for Phase I or Phase II applications will
be based on quality of the proposed project as determined by peer review,
availability of funds, and program priority.

FAST TRACK, Phase II applications may be funded following submission of the Phase
I progress report and other documents necessary for continuation.  Phase II
applications will be selected for funding based on the initial priority score,
NCI's assessment of the Phase I progress and determination that Phase I goals
were achieved, the project's potential for commercial success, and the
availability of funds.

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
6130 Executive Boulevard, 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:

Ms. Kathleen Shino
National Cancer Institute
6120 Executive Boulevard, Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 248
FAX:  (301) 496-8601
Email:  shinok@gab.nci.nih.gov

Direct inquiries regarding review matters to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636 - MSC7407
Bethesda, MD  20892-7407
Rockville, MD  20852 (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.  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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