CEREBRAL RADIOBIOLOGY AND NEUROIMAGING OF BRAIN TUMORS

Release Date:  July 29, 1998

PA NUMBER:  PA-98-094

P.T.

National Institute of Neurological Disorders and Stroke
National Cancer Institute

PURPOSE

The National Institute of Neurological Disorders and Stroke (NINDS), and the
National Cancer Institute (NCI) invite applications for support of research that
will increase our knowledge of the genetic, molecular, cellular, and
physiological mechanisms of radiation-induced cell injury and recovery, and the
sensitizing and protective mechanisms in the central nervous system under
radiation treatment conditions for brain tumors.  The intent of this program
announcement (PA) is to encourage investigator-initiated applications to study
tumor and normal brain cell injury and repair mechanisms induced by brain tumor
radiotherapy including stereotactic radiosurgery procedures such as the Gamma
Knife, altered fractionation and/or radioenhancing agents, using state-of-the-art
neurobiological and neuroimaging approaches.

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, Cerebral Radiobiology and
Neuroimaging of Brain Tumors, is related to the priority areas 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.  Foreign institutions are not eligible for program project
(P01) grants.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

The support mechanisms for grants in this area will be the investigator-initiated
research project grant (R01) and the program project grant (P01).  The principal
investigator and any participating investigators, will plan, direct and perform
the research.  Applicants for program project and research center grants are
encouraged to contact the NINDS or NCI representative listed under INQUIRIES as
early as possible in the planning stages.

An applicant planning to submit a new (Type 1) investigator-initiated grant
application requesting $500,000 or more in direct costs for any year is advised
that he or she must contact Institute program staff (see INQUIRIES, below) before
submitting the application, i.e, as plans for the study are being developed. 
Furthermore, the applicant must obtain agreement from Institute staff that the
Institute will accept the application for consideration for award.  Finally, the
applicant must identify, in the cover letter that is sent with the application,
the staff member and Institute who agreed to accept assignment of the
application.

RESEARCH OBJECTIVES

Background

Malignant glial tumors are a highly invasive, rapidly lethal form of brain tumor
that have defied therapeutic inroads for the past four or five decades.  These
neoplasms are biologically unusual in that they rarely metastasize outside the
neuraxis yet are capable of invasion of the brain parenchyma.  Most forms of
brain tumor radiotherapy, such as stereotactic radiosurgery, are targeted at the
proliferative tumor cells. Nevertheless, proliferation and invasiveness of
gliomas and the threat of damage to normal surrounding normal brain tissue caused
by therapeutic interventions are major causes of treatment failure.  Considerable
attention to these problems will be needed before gains in therapy can be
realized.

Radiation therapy is the most effective current adjuvant to surgery for the
treatment of malignant brain tumors.  However, damage to normal, non-targeted
tissue limits the utility of this therapeutic approach.  Theoretically, novel
neurobiological approaches that would prevent or decrease normal cell toxicity
or enhance tumor cell toxicity would allow for the delivery of higher doses of
radiation and thus, improve therapeutic efficacy.  Stereotactic radiosurgery can
achieve destruction of a defined intracranial target through precise targeting
of ionizing irradiation with minimal damage to surrounding tissue.  As a result
of advances in high-resolution neuroimaging and improved use of stereotactic
guiding techniques, this procedure is being used increasingly as an alternative
to either conventional surgical resection or fractionated radiation therapy for
primary meningiomas and metastatic brain tumors.  Radiosurgery is also being used
in the multi-modality management of patients with malignant gliomas.  While
stereotactic radiosurgery is minimally invasive, it is not risk-free and warrants
further evaluation to identify strategies to enhance treatment outcomes and
reduce risks.

The pathogenesis of radiation-induced brain injury is not clear, but DNA damage
is likely one of the underlying causes of radiation injury.  Two prominent
aspects of radiation injury to the brain are vascular damage, observed as blood-
brain barrier breakdown and ischemia-like alterations and demyelination of the
white matter.  It is unclear whether endothelial cells or oligodendrocytes are
particularly sensitive to radiation-induced damage or if other cells, such as
neurons, smooth muscle cells and astrocytes that surround blood vessels within
the brain are also vulnerable.  The degree to which exogenous factors or
intrinsic molecular characteristics make cells particularly susceptible to
radiation injury is also unknown.  Furthermore, recent work suggests that the
brain has the capability for limited repair by progenitor cells that can
differentiate to form oligodendroglia, astrocytes, or neurons.  It is unknown
whether damage to these cells contributes to radiation injury, or if these cells
can be induced to repair injury.

Knowledge of how the brain works is increasing exponentially due to the rapid
growth and recent advances in the neuroscience field.  Progress in basic
neurobiology and neuroimaging research is providing insight into the inordinately
complex molecular, cellular and physiological processes involved in the central
nervous system (CNS).  Scientific advances in developmental neurobiology with
regard to cell lineage, signal transduction and molecular genetics and advances
in functional MRI and PET may be particularly productive lines for investigating
the susceptibility or resistance of specific brain tumor and non-tumor cells to
radiation.

Radiation injury to the brain develops over months with a variable latency
between irradiation and damage.  Advances in neuroimaging have contributed to our
understanding of the physiology of brain disorders with particular emphasis on
blood flow and energy metabolism.  However, very little is known about the
physiology of brain tumor following conventional radiation therapy or
stereotactic radiosurgery using advanced neuroimaging methods. The development
of neuroimaging methods to serially study humans and animals and their
cerebrovascular physiology could provide a powerful tool to measure changes in
blood flow, blood flow response to physiologic manipulations, blood-brain and
blood-tumor barrier function, development of edema, and tissue necrosis following
irradiation.

Therefore, the intent of this program announcement is to solicit applications for
research to improve our knowledge of the biological basis of brain tumor cell
function and surrounding normal brain cell injury and repair mechanisms induced
by radiotherapy, including stereotactic radiosurgery, for brain tumor treatment
using state-of-the-art neurobiological and neuroimaging  approaches.  These
investigations may provide opportunities for the development of novel and
improved therapies to enhance tumor cell death or reduce CNS injury in healthy
brain cells adjacent to the targeted tumor cells.

Scope and Objectives
Investigators with diverse scientific interests are invited to apply their
expertise to basic, translational and clinical research to improve our knowledge
of the genetic, molecular, cellular, and physiological mechanisms of radiation-
induced tumor and normal brain cell injury, recovery, and protective mechanisms
in the central nervous system against radiation damage.  Applications to study
tumor and normal brain cell injury and repair mechanisms induced by radiotherapy
using state-of-the-art neurobiological and neuroimaging  approaches are
encouraged.  Examples that illustrate possible areas of research to be considered
are presented below.  They are intended only to provide a broad direction for
research into the effects of radiation on brain tumor and should be considered
illustrative and not restrictive.

o  Identify the tissues, cells, and substrates critical to radiation
susceptibility and resistance;

o  Investigate the mechanisms of radiation-induced damage and repair in glia,
neurons, endothelia, smooth muscle cells and other brain cells;

o  Investigate the immune, inflammatory, neuron, glial and glioma cell-cell
interactions and identifying novel glia-specific antigens;

o  Investigate the role of inflammation and the complex network of cytokines in
radiation induced brain injury and repair mechanisms;

o  Clarify the causal relationships between DNA damage and pathological CNS
responses to tumors;

o  Identify the genes, enzymes, and receptors that contribute to DNA injury and
repair in brain tumor cells, neurons and vascular wall cells;

o  Study the interactions of brain extracellular matrix proteins and trophic
factors in glial and glioma cell function in the brain with and without
radiation;

o  Explore the biology of neural precursor cells to include the regulation of
growth, migration and differentiation in the irradiated brain;

o  Study the effects of chemotherapeutic agents, that commonly cause DNA damage
or alter DNA repair, on radiation sensitivity of normal brain;

o  Study the effects of radiosensitizing and neuroprotective agents in the
irradiated brain;

o  Elucidate gene and protein expression in glia, neurons, endothelia and smooth
muscle cells during glial and glioma migration, proliferation, differentiation;

o  Investigate molecular/genetic mechanisms of  radioresistance and
susceptibility in brain tumor cells;

o  Explore the functional characterization of glia and glioma cells through
electrophysiological approaches;

o  Investigate the role of the blood-brain-barrier and angiogenesis in cell and
tissue survival;

o  Identify imaging methods to measure gene expression non-invasively in the
brain (e.g. SPECT, MRI);

o  Explore the biological basis for cognitive loss following brain radiation;

o  Explore physiological responses of brain tumors with advanced neuroimaging
methods;

o  Identify clinical outcomes and define outcome measures associated with
stereotactic radiosurgery for the treatment of primary and recurrent brain
tumors;

o  Identify patient selection factors (location, tumor volume, grade, etc.)
associated with tumor response and survival differences in patients treated with
stereotactic radiosurgery compared to standard radiation therapy.

Applicants are encouraged to develop and use new or refined animal models,
methodologies, instrumentation, and procedures that will reveal brain specific
mechanistic details of the proliferative and migratory process.  Basic,
translational, or clinical studies to improve glial growth control, prevent
molecular pathophysiological changes, or restrain cell migratory behavior are
welcome.

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
sub-populations 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 was 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 from these sources or
from the program staff or contact person listed under INQUIRIES.  Program staff
may also provide additional relevant information concerning this 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 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.

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

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted on the standard application receipt dates as indicated
in the application kit.  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:
GrantsInfo@nih.gov.

Check YES in item 2 on the face sheet of the application and type in the number
and title of the PA.

Applicants for the P01 grants should contact the NINDS and NCI program directors
listed under INQUIRIES to discuss their planned projects and to request the
Institute's guidelines for program project.

Submit a signed, typewritten original of the application, including the
Checklist, plus five 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health Service
referral guidelines.  Applications that are complete will be evaluated for
scientific and technical merit by an appropriate peer review group convened in
accordance with 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 those applications deemed to have the highest scientific merit will be
discussed, assigned a priority score, and receive a second level review by the
appropriate national advisory council or board.

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.

o  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?

o  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?

o  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?

o  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)?

o  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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

o  Adequacy of plans to include both genders, minorities and their subgroups, and
children as appropriate for the scientific goals of the research.  Plans for the
recruitment and retention of subjects will be evaluated.

o  The initial review group will also examine the provisions for the protection
of human and animal subjects, and the safety of the research environment.

o  Availability of special opportunities for furthering research programs through
the use of unusual talent resources, populations, or environmental conditions in
other countries which are not readily available in the United States or which
provide augmentation of existing United States resources.

o  For program project grant applications, additional factors to be considered
during the review include the efficacy of the collaboration, the commitment of
the participants to the collaboration, the design and responsibilities of the
coordinating center and the cost effectiveness of the collaborative effort.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be used in making funding decisions:

o  Scientific and technical merit of the proposed project as determined by peer
review
o  Availability of funds
o  Program balance among research areas of the program announcement

INQUIRIES

Written, telephone, and Email inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding scientific and programmatic issues to:

Dr. Thomas P. Jacobs
Division of Stroke, Trauma and Neurodegenerative Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8A13
Bethesda, MD  20892
Telephone:  (301) 496-4226
FAX:  (301) 480-1080
Email:  TJ12G@NIH.GOV

Dr. Francis J. Mahoney
Division of Cancer Treatment and Diagnosis
National Cancer Institute
6130 Executive Boulevard, Room 800
Rockville, MD  20852
Telephone:  (301) 496-9360
FAX:  (301) 480-5785
Email:  FM43q@NIH.GOV

Questions concerning fiscal aspects of this PA may be addressed to:

Ms. Kathleen Howe
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
Email:  KH52X@NIH.GOV

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.853, 93.854, and 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
99-150, 42 USC 241 and 285) and administered under PHS grant 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 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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