FULL CODING SEQUENCES OF GENES TO FACILITATE CANCER RESEARCH

NIH Guide, Volume 26, Number 39, December 5, 1997

RFA:  CA-98-004

P.T.

National Cancer Institute

Letter of Intent Receipt Date:  February 5, 1998
Application Receipt Date:  March 12, 1998

PURPOSE

The Technology Development Branch of the Cancer Diagnosis Program, Division of
Cancer Treatment and Diagnosis at the National Cancer Institute (NCI) invites
applications proposing strategies for the cost-effective generation of full
coding sequences of genes that may be useful for cancer research.  This RFA is
intended to support sequencing efforts which will provide high quality full
coding sequences of genes to the research community in a systematic and timely
way.  Full coding sequences are defined as the assembled complete sequence of all
the exons for a given gene (or any naturally occurring splice variant).  Full
coding sequences may be derived from single full length cDNA clones or they may
be sequences assembled from partial clones which span the entire coding sequence
of a gene.

Investigators applying for this RFA must provide a plan to scale up and modify
their current sequencing strategies to retrieve, prioritize and sequence cDNA
clones in a high throughput manner. Proposed sequencing strategies must include
mechanisms to assure that the final sequences are of high quality and methods to
determine that the final sequences contain the full coding sequence of the genes. 
Investigators must also include a rationale for selecting genes to be sequenced
based on their potential relevance to cancer research.  While long-range gene
selection strategies are being devised and tested, it is expected that initial
sequencing efforts will focus on genes which have been previously identified as
potentially relevant to cancer.

Grants will be awarded using the R01 funding mechanism. A total of $2.5 million
per year will be available to support approximately five awards.  This RFA will
support projects for up to three years to develop high throughput, cost effective
systems for sequencing selected genes. At or before the end of three years,
program staff will convene a review to evaluate project progress.  Based on this
review, the NCI will consider mechanisms to support further large scale cDNA
sequencing efforts.  Such support will be contingent on successful demonstration
by the grantees of the cost effective production of high quality sequences
coupled with a long range plan for selecting genes to be sequenced.

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 Request for Applications (RFA), Full
Coding sequences of Genes to Facilitate Cancer Research, 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 and foreign, 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

Support for this program will be through the National Institutes of Health (NIH)
research project grant (R01) mechanism.  The total project period for an
application submitted in response to this RFA may not exceed three years.  The
anticipated award date is July 1, 1998.

This RFA is a one-time solicitation.  However, if there is sufficient continuing
program need, NCI will invite recipients of awards under this RFA to submit
competing continuation applications for review as described in REVIEW
CONSIDERATIONS. Unsolicited competing continuation applications will compete with
all investigator-initiated applications and will be reviewed according to the
customary peer review procedures.  Awards will be administered under PHS grants
policy as stated in the Public Health Service Grants Policy Statement, DHHS
Publications No. (OASH) 94-50,000, revised April 1, 1994.

FUNDS AVAILABLE

It is anticipated that a total of $2.5 million (total costs per year) will be
available.  Approximately five awards are expected to be made from the pool of
applications received.  The number of awards made will be contingent upon the
quality of the applications received and the availability of funds.

RESEARCH OBJECTIVES

Background

The rapid increase in our understanding of tumor biology coupled with the
technology and data emerging from the human genome project offer the opportunity
for a change in the way cancer research is done.  It is becoming clear that
cancer is not a single disease but many, and that cancers arise from the gradual
accumulation of genetic changes in single cells.  It is not clear which changes
and how many changes are required to cause an invasive cancer.  Defining which
genes are involved in the initiation and progression of cancer remains a
challenge.

The NCI has established the Cancer Genome Anatomy Project (CGAP) to capitalize
on the technology and data emerging from the human genome project and to direct
them toward cancer research.  One initial focus of CGAP has been the
establishment of the Tumor Gene Index:  a collection of expressed sequence tags
(ESTs) from genes expressed in normal, precancerous, and cancerous tissues.  ESTs
are valuable in that they allow a rapid preliminary identification of a large
number of expressed genes. They are limited in that the sequence, and sometimes
the clones, represent only partial genes.

Currently, individual investigators who have identified a potentially useful
gene, often from an EST,  must spend considerable time and funds to isolate,
sequence and assemble clones containing the full coding sequence before they can
proceed with the biological evaluation of the gene.  An organized system to
rapidly provide investigators with full length sequences and clones will
facilitate the rapid analysis and characterization of these potentially useful
genes.  The initial issuance of this RFA (CA-97-012) was focused on the
development of technology to generate full length, representational cDNA
libraries from which full length sequences could be obtained.  The development
of such libraries is technically challenging and significant barriers must be
overcome before these libraries become available.  This reissuance takes
advantage of a complementary, immediate opportunity to generate high quality
sequences for use by the cancer community from existing libraries.  The projects
supported by this RFA will provide important reagents to the research community
while the technologies for generating more comprehensive full length cDNA
libraries progress.

Research Objectives

This RFA is intended to support the cost-effective generation of full coding
sequences from genes that may be important in cancer biology.  Investigators
should devise a long term strategy for selecting genes to be sequenced based on
their potential usefulness to cancer research.  Applicants may choose, for
example, to focus on genes expressed in tumors from specific sites or on members
of specific gene pathways or gene families that may be involved in cancer biology
(e.g. cell cycle genes).  Applicants may also propose selection strategies that
utilize emerging technologies such as expression arrays or differential display
to identify genes which are differently regulated during cancer progression.
While long-term gene selection strategies are being devised and tested,
applicants should focus their efforts on sequencing genes which have been
previously identified as potentially relevant to cancer. Initial gene targets
could include but are not limited to genes identified by ESTs or other partial
sequences for which there is a rationale to assume cancer relevance (e.g. strong
sequence homology to an identified tumor suppressor gene).  Although some
unintentional duplication may be unavoidable, applicants should not knowingly
sequence genes for which a complete, high quality sequence already exists. In an
attempt to reduce redundancy between sequencing efforts, NCI will facilitate the
coordination of these efforts.

Applicants should also propose strategies for improving the efficiency of current
technologies for generating full coding sequences of genes.  Strategies could
include but are not limited to selecting full length clones from cDNA libraries,
devising more efficient sequencing strategies or improving sequence assembly.
Applicants are required to define criteria they will use to demonstrate that they
are obtaining the complete, fully assembled, coding sequence of the genes.  They
are also asked to define criteria they will use for assessing final sequence
quality.  Finished sequence quality should have an error rate not higher than one
error in 10,000 bases.  Finally, applicants will be required to make available
the full assembled sequence and clones from which the sequences are derived in
a timely manner.  Clones already publicly available need not be made available
in a separate way but should be clearly identified.  Clones which are developed
specifically for this project or which are  not otherwise available, will be made
available through the CGAP distribution network.  Final assembled sequences
should be submitted to Genbank on a regular basis: every two weeks or in batches
of ten clones, which ever comes first.  Finally, all projects must show the
potential for effectively scaling up the sequencing effort.  Early stages of the
projects may require applicants to spend time devising selection strategies and
thus fewer sequences may be produced.  As projects progress, sequencing efforts
should be able to produce sequences at a rate of several hundred finished
sequences per year.

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 may also obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 5, 1998, 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 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:

Jennifer Couch, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 700, MSC 7388
Bethesda, MD  20892
Telephone:  (301) 402 4185
FAX:  (301) 402 7819
Email:  jc332a@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  Applications 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.

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 form 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 (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must be sent
to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7399
Rockville, MD  20850 (for express/courier service)

Applications must be received by March 12, 1998.  If an application is received
after that date, it will be returned to the applicant without review.  The Center
for Scientific Review (CSR) 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 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 applications will be returned to the
applicant without further consideration.  If the application is not responsive
to the RFA, CSR staff may contact the applicant to determine whether to return
the application to the applicant or submit it for review in competition with
unsolicited applications at the next review cycle.  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 NCI in accordance with
the review criteria stated below.

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 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?

Additional Review Criteria Specific for this RFA:

1.  The adequacy of the plan for generating high quality sequence and for
assessing sequence quality.

2.  The validity of the criteria for determining that the final sequences are the
complete coding sequence of the expressed gene.

3.  The feasibility and merit of the strategy for choosing clones to be sequenced
based on their potential relevance to cancer.

4.  The potential of the proposed project to rapidly scale up to high throughput
and cost effective sequencing of full coding sequences.

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 provisions
for the protection of human and animal subjects; and the safety of the research
environment.

AWARD CRITERIA

Selection of applications for award will be based on their scientific and
technical merit reflected in the priority score as determined by peer review, the
degree to which it meets the goals of the RFA, other programmatic considerations
and the availability of funds.

Schedule

Letter of Intent Receipt Date:             February 5, 1998
Application Receipt Date:                  March 12, 1998
Review by National Cancer Advisory Board:  May 1998
Anticipated Award Date:                    July 1, 1998

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:

Jennifer Couch, Ph.D.
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Suite 700, MSC 7388
Bethesda, MD  20892
Telephone:  (301) 402 4185
FAX:  (301) 402 4185
Email:  jc332a@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Teresa Mercogliano
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Room 243, MSC 7150
Bethesda, MD  20892
Telephone:  (301) 496 7800, ext. 243
FAX:  (301) 496 8601
Email:  mercoglt@gab.nci.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.394.  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 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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