ENGINEERED ISOGENIC CELL LINES WITH RELEVANT CANCER TARGETS

Release Date:  May 11, 1998

PA NUMBER:  PAR-98-068

P.T.

National Cancer Institute

Letter of Intent Receipt Dates:  July 2, 1998 and March 5, 1999
Application Receipt Dates:  August 7, 1998 and April 9, 1999

PURPOSE

This Program Announcement (PA) encourages the small business community to develop
isogenic cell lines in which functions of a molecular activity or pathway found
in human tumors can be analyzed in pair-wise fashion.  Such cell lines could be
used for drug screening with the intent of identification of compounds which
influence the action of the identified target.  The end result of the PA-
supported projects would be a series of genetically engineered screening models
which the small businesses could market directly or utilize in a license
agreement or other type of collaboration.

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, Engineered Isogenic Cell Lines
with Relevant Cancer Targets, 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 "Healthy People 2000" (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, independently owned by United States citizens and located in the United
States, 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 PA 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

Previous drug screening paradigms have utilized anti-proliferative activity in
in vitro and/or in vivo models and, more recently, have included structure-based
approaches directed at expressed macromolecular targets as the basis for initial
drug discovery.  While each of these approaches has distinct advantages and
disadvantages, the relationship of the drug lead to the pathophysiology of the
cancer cell is less clear than might be possible if screening models with defined
interacting molecular targets and regulatory pathways were available.  Certain
of the pathways altered in cancer cells have been defined.  For example, deletion
or mutation of p53 leads to a defect in response to DNA damage; alterations in
the Rb tumor suppressor protein occurs reciprocally in relation to deletion of
certain members of the E2F family of transcriptional regulators; persistence of
bcl-2 family member expression leads to defective apoptosis; and the bcr-abl
chimeric molecule activates several growth regulatory pathways, including PI-3
kinase and myc-dependent activities.

It would be desirable to create otherwise isogenic cell lines where specific
molecular alterations found in tumors could be displayed in a cellular context
which would allow molecular analysis of a particular function, such as, but not
limited to, growth dependence.  Engineered cell lines could be employed for
discovery of compounds which influence the action of the defined molecular
alteration without confounding variables of different pathways frequently
operative in tumor cells.  Comparison of relative activity of specific agents in
the paired cell lines derived from human tumors would provide insight about the
importance of the molecular target under evaluation in human cancers.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included  in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the research.  This
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

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 the
NIH, unless there are clear and compelling scientific and ethical reasons not to
include them.  This policy applies to all initial (Type 1) applications submitted
for receipt dates after October 1, 1998. Therefore, the policy does not apply to
applications submitted on the August 7, 1998 receipt date.

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://www.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by the dates listed at the beginning
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 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

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
[email protected].  Helpful information in preparation of the application can be
obtained at: 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 August 7, 1998, and April 9, 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 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), 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 Phase II SBIR award, $750,000 and two years.  The
normal level of support and period of time for a Phase I STTR awards 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;
https://grants.nih.gov/grants/guide/notice-files/not98-014.html

Applicants who plan to submit a Phase II SBIR or STTR application requesting
$500,000 or more per year are advised that it is important that they contact
program staff listed in the OMNIBUS SOLICITATIONS as they begin to develop plans.
Applications received without prior staff contact may be delayed in the review
process or returned to the applicant without review (NIH GUIDE, Volume 22, Number
45, December 17, 1993).

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. 
If so, the applicant may apply later for Phase II support.  Such applications
will be reviewed by a standard Study Section of the Center for Scientific Review
(CSR) or by a special review group convened in response to a re-issuance of this
PA, if applicable.

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 copies must be sent or
delivered to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040
Bethesda, MD  20892-7710
Bethesda, MD  20817-7710 (for express/courier service)

To expedite the review process, at the time of submission, send one additional
copies of the application to:

Ms. Toby Friedberg
Referral Officer
National Cancer Institute
6130 Executive Boulevard, Room 636a,
Bethesda, MS 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 beginning of
this program announcement.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the 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 one or more
Special Emphasis Panels (SEP) 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,
which will be sent to the Principal Investigator.  Following scientific-technical
review, the applications will receive a second-level review by the National
Cancer Advisory Board or by the another IC review Board if the application is not
assigned to 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 this PA.  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.

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 or 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.

The SEP will also examine: the appropriateness of the 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 provisions for the protection of
human and animal subjects; and the safety of the research environment.   In
addition, for  applications submitted for April 9, 1999 receipt date, reviewers
will be instructed to address the adequacy of plans for including children as
appropriate for the scientific goals of the research, or justification for
exclusion (see section on  NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN
AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS).

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:  [email protected]

Direct inquiries regarding fiscal matters to:

Ms. Kathleen Shino
National Cancer Institute
6130 Executive Boulevard, Room 243
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 248
FAX: (301) 496-8601
Email: [email protected]

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:  [email protected]

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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