GENETIC MECHANISMS IN ORAL CANCER

Release Date:  January 9, 1998

RFA:  DE-98-008

P.T.

National Institute of Dental Research

Letter of Intent Receipt Date:  March 1, 1998
Application Receipt Date:  June 10, 1998

PURPOSE

The National Institute of Dental Research (NIDR) invites investigator-initiated
research grant applications for investigation of genetic mechanisms involved in
the initiation and progression of oral cancer, the invasion by and metastasis of
oral cancer cells, the recurrence of oral cancer, the occurrence of second
primary lesions and the development of gene therapy for these malignancies. 
Applications are also encouraged for the development and application of genetic
markers for diagnosis and prognosis.

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),
Genetic Mechanisms in Oral Cancer, is related to the priority area of oral
health.  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 all domestic and foreign, for-profit and non-
profit organizations, public and private, including universities, colleges,
hospitals, laboratories, units of state and local governments and eligible
agencies of the Federal government.  The NIDR encourages applications that
include investigators who are racial/ethnic minority individuals, women, and
persons with disabilities.  Applications are not restricted to traditional
dental, oral and craniofacial research settings.

MECHANISM OF SUPPORT

The mechanisms of support for applications in response to this RFA are individual
research project grants (R01).  Choice of an appropriate area and the direction
and execution of the proposed activities are solely the responsibility of the
applicant. This RFA is a one-time solicitation by NIDR and applicants may apply
for and receive up to five years of support.  Future competitive renewal
applications will compete with all investigator-initiated applications and will
be reviewed according to customary referral and review procedures.  New
investigators without prior R29 or R01 support are strongly encouraged to apply. 
The National Cancer Institute (NCI) will receive secondary assignments on
applications in response to this RFA that meet the referral guidelines for the
NCI. The earliest possible award date will be April 1, 1999.

FUNDS AVAILABLE

It is anticipated that the NIDR will allocate approximately $3 million in total
(direct plus indirect) costs to support projects from this RFA provided that a
sufficient number of applications of high scientific merit are received. 
Requested increases in direct costs for subsequent years may not exceed three
percent.  Although support for this program is provided for in the financial
plans of the NIDR, the award of grants pursuant to this RFA is contingent upon
the availability of appropriated funds.  Policies that govern research grant
programs of the National Institutes of Health (NIH) will prevail.

RESEARCH OBJECTIVES

Background

Each year approximately 9,000 deaths are attributed to oral cancer, a rate which
exceeds that for cervical cancer, malignant melanoma and Hodgkin~s disease. More
than 90% of these malignancies are squamous cell carcinomas.  The prognosis for
patients with oral malignancies continues to be poor with only approximately 50%
survival at five years.  Unfortunately, this survival rate has not changed
substantially in recent decades.  Like most epithelial neoplasms, the incidence
of oral squamous cell carcinoma is age related, rising dramatically above age 65.

Unlike many anatomic sites, the oral cavity is readily accessible for physical
examination by health care personnel, a fact which should facilitate the early
identification of pre-malignant lesions as well as the early diagnosis and less
radical treatment of malignancies.  However, most lesions are not detected until
they are advanced or have metastasized.  At these stages the effectiveness of
chemotherapy, radiotherapy and surgery or combinations of these modalities has
been disappointing.  Moreover, successful therapy of oral cancer has been
significantly hindered by the subsequent development of second primary tumors,
the major determinant for treatment failure and death.

Oral cancer is one of the most severely debilitating forms of malignancy.  It is
often associated with extensive destruction of oral and facial structures and
further disfigurement may result from surgical removal of affected tissues.
Additionally, serious side effects are associated with the currently utilized
chemotherapeutic and radiotherapeutic regimens.  Thus, the sequelae of oral
cancer and the current clinical approaches to its treatment include not only
facial mutilation, with its resultant social and psychological implications, but
also impairment or loss of salivary gland function, diminution of immune function
and detrimental effects on speech, swallowing and breathing.  These factors all
contribute to a marked decline in general health and quality of life.

Like other malignancies, oral cancer is initiated and progresses through a series
of discrete, irreversible and complementary alterations in genes that control
cell growth, differentiation and motility.  Certain pertinent genetic events
provide cells with a selective growth advantage resulting in proliferation of a
dominant clone of cells.  The occurrence of subsequent genetic alterations
enhances tumor cell survival and promotes invasion and metastasis.  However,
these events remain poorly defined.

Goals and Objectives

Research directed towards the elucidation of the genetic mechanisms involved in
the initiation, progression and recurrence of oral cancer, the occurrence of
second primary lesions as well as invasion by and metastasis of oral cancer cells
is an essential prerequisite for the design of appropriate therapeutic strategies
for oral malignancies.  It is the intent of this RFA to stimulate innovative
research that will reduce the morbidity and mortality of oral cancer through such
research.  It is anticipated that the research submitted in response to this
announcement will also include application of the findings to the development of
biomarkers for the detection of pre-malignant lesions and the early detection of
malignancies as well as for the development of prognostic indicators.  Although
not inclusive or restrictive, the following would be appropriate topics for this
RFA:

o  genetic basis for the conversion of normal cells to those expressing pre-
malignant phenotypes;
o  genetic basis for the initiation of oral cancer by risk factors, e.g.,
viruses, tobacco, alcohol;
o  aberrations in genes implicated in cell cycle control pathways including
apoptosis;
o  mechanisms of regulation of cell cycle control genes;
o  sequential genetic and functional changes during the initiation and
progression of oral cancer;
o  mechanisms of induction of DNA damage and repair;
o  molecular mechanisms involved in oral cancer cell attachment, invasion and
metastasis;
o  molecular studies of angiogenesis;
o  identification of novel tumor suppressor genes and functional studies of the
proteins that they encode;
o  development of diagnostic and prognostic genetic indicators;
o  gene therapy for oral cancer; and
o  genetic basis for immunomodulation and immunosuppression of oral cancer.

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, Vol. 23, No.
11, March 18, 1994.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 1, 1998, a letter of intent
that includes a descriptive title of the proposed research, the name, mailing
address, FAX, email address and telephone number of the Principal Investigator,
the identities of other key personnel and participating institutions and
departments if appropriate; and the number and title of this RFA.

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 is
helpful in estimating the potential review workload and avoiding conflict of
interest in the review.

The letter of intent is to be sent to Dr. Ann L. Sandberg at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  These forms 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: 
ASKNIH@od.nih.gov).

The RFA label available in the PHS 398 application kit must be affixed to the
bottom of the face page of the original and the original must be placed on top
of the entire package.  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, in order to identify the application as a response
to this RFA, the RFA title (Genetic Mechanisms in Oral Cancer) and number DE-98-
008 must be typed in item 2 of the face page of the application form and the YES
box must be checked.  The instructions accompanying Form PHS 398 must be followed
as far as possible.

Submit a signed, typewritten original of the application, including the checklist
and three signed photocopies in one package 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)

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

Dr. H. George Hausch
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN-38D - MSC 6402
Bethesda, MD  20892-6402

Applications must be received by June 10, 1998.  If an application is received
after that date, it will be returned to the applicant without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the NIH Center
for Scientific Review (CSR) and responsiveness by the NIDR.  If NIDR staff finds
that the application is not responsive to the RFA or is incomplete it will be
returned without further consideration.

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 NIDR in accordance with the review criteria stated below.  As part of the
initial merit review, applications may be subjected to a streamlined review
process to determine their scientific merit relative to other applications
received in response to the RFA.  The NIDR will withdraw those judged to be in
the bottom tier of applications.  Those determined to be competitive will be
evaluated for scientific and technical merit by the review committee.  Secondary
review of the applications will be conducted by the National Advisory Dental
Research 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 and 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.

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?

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?

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?

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)?

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?

The initial review will also examine:  the appropriateness of proposed 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

The earliest anticipated date of award is April 1, 1999.  Applicants should be
aware that, in addition to scientific merit, program priorities and program
balance, the total cost of the proposed project and the availability of funds
will be considered by the NIDR staff and the National Advisory Dental Research
Council in making funding recommendations.  In addition, the NIDR values
complementary funding from other public and private sources including foundations
and industrial concerns.  In circumstances in which applications have similar
scientific merit, but vary in cost-competitiveness, the NIDR is likely to select
the more cost-competitive applications for funding.

INQUIRIES

Written, email and telephone 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:

Dr. Ann L. Sandberg
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN-24A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2419
FAX:  (301) 480-8318
Email:  ann.sandberg@nih.gov

Dr. Cheryl L. Marks
Division of Cancer Biology
National Cancer Institute
Executive Plaza North, Room 501
Bethesda, MD  20892-7381
Telephone:  (301) 435-5226
FAX:  (301) 496-8656
Email:  cm74v@nih.gov

Direct inquiries regarding grants management issues to:

Mr. Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
45 Center Drive, Room 4AN-44A, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Martin.Rubinstein@nih.gov

Schedule

Letter of Intent Receipt Date:  March 1, 1998
Application Receipt Date:       June 10, 1998
Scientific Review Date:         August 1998
Advisory Council Date:          January 1999
Earliest Award Date:            April 1, 1999

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.121.  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.  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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