Progress

Review

Groups

Report of the

Brain Tumor

Progress Review Group

November 2000
From the Leadership: 

It is a great pleasurdfce to submit this Report of the Brain Tumor Progress Review Group (BTPRG) to the Director and Advisory Committee to the Director of the National Cancer Institute 

(NCI), and to the Director and National Advisory Neurological Disorders and Stroke Council of 

the National Institute of Neurological Disorders and Stroke (NINDS). At the beginning of 1999, 

the BT-PRG accepted the charge of Dr. Richard Klausner, Director of the NCI, and Dr. Gerald 

Fischbach, Director of the NINDS, to develop a national plan for the next decade of brain tumor 

research. Although this is the 4th in the series of PRGs, it is the first to be sponsored by 2 

institutes, reflecting the importance of both cancer biology and neurobiology to the brain tumor 

field. The expertise and efficiency of the BT-PRG members and of the participants of the BTPRG Roundtable Meeting have produced this exciting report in a ten-month period, reflecting the 

energy and enthusiasm of the clinical, research, industrial and advocacy communities for finding 

a cure for brain tumors. 

The Report of the Brain Tumor Progress Review Group highlights the scientific research 

priorities that represent the next steps toward understanding the biological basis of brain tumors, 

and toward developing effective therapies for brain tumors. We look forward to discussing these 

priorities with the leadership of the NCI and NINDS. 

Respectfully, 

David N. Louis, M.D. Jerome Posner, M.D. Thomas Jacobs, Ph.D. Richard Kaplan, M.D. 

Co-chair, PRG Co-chair, PRG Executive Director, PRG Executive Director, PRG 

National Institute of National Cancer Institute 

Neurological Disorders 

and Stroke 


Foreword

This report represents the collaborative efforts of scientists, clinicians, industry representatives, 

and patient advocates who were charged by the National Cancer Institute and the National 

Institute of Neurological Disorders and Stroke with the task of setting overall priorities for brain 

tumor research. The report and its appendices highlight those priorities in light of the biological 

and clinical complexity of brain tumors and the formidable challenges that have slowed progress 

toward their cure. Many priorities and directions need to be pursued in brain tumor research, and 

these are discussed in the appendices. Common themes emerge, however, and the Brain Tumor 

Progress Review Group considers the priorities delineated in this report to be the best guide to 

the future direction of brain tumor research. This report, and additional related information are 

available at the Brain Tumor Progress Review Group Web site 

(http://osp.nci.nih.gov/Prg_assess/PRG/BTPRG. The reader also is referred to the Web sites of 

the National Cancer Institute (www.nci.nih.gov) and the National Institute of Neurological 

Disorders and Stroke (www.ninds.nih.gov). 
Acknowledgments 

The Report of the Brain Tumor Progress Review Group (BT-PRG) is the product of work carried 

out over the past 10 months by the BT-PRG, the participants at the BT-PRG Roundtable 

Meeting, and the staffs of the National Cancer Institute (NCI) and the National Institute of 

Neurological Disorders and Stroke (NINDS). The report is based on meetings of the BT-PRG 

Leadership in Bethesda, Maryland, in February 2000; of the BT-PRG in Bethesda in March 2000; 

of the Roundtable Meeting participants in Leesburg, Virginia, in July 2000; and of weekly 

conference calls of the BT-PRG Leadership and NCI staff from February through October 2000. 

Special thanks are extended to the NCI Office of Science Planning and Assessment in the Office 

of Science Policy for their extraordinary organization and direction in all phases of the BT-PRG 

process. In particular, the guidance of Kate Nagy and Susan Rossi and the leadership of Cherie 

Nichols has been invaluable. The completion of the report was also greatly facilitated by Deborah 

Shuman, who served as lead science writer, and the breakout session reports by Deborah Shuman 

and the other expert science writers who attended the Roundtable Meeting. 

Particular thanks are also due to the co-chairs of the Roundtable Meeting breakout sessions, who 

worked diligently with the BT-PRG members to plan the breakout sessions and formulate the 

individual breakout session reports. 

Finally, the BT-PRG recognizes the tremendous efforts of brain tumor patient advocacy groups 

in strongly encouraging the NCI and NINDS to begin the BT-PRG process and in their 

invaluable participation in many aspects of the work. 
Table of Contents

About the Brain Tumor Progress Review Group ...................................1

REPORT OF THE BRAIN TUMOR PROGRESS REVIEW GROUP .................3

Appendix: Full Reports of the BT-PRG Breakout Sessions 

Cancer Biology and Etiology .............................................. 15

Therapeutic Targeting, Blood-Brain Barrier, 

Gene Therapy, and Vascular Biology ................................. 19

Detection and Diagnosis ................................................. 24

Epidemiology, Prevention, and Outcomes .................................... 28

Cancer Genetics and Epidemiology .........................................34

Imaging ..............................................................37

Tumor Immunology .....................................................52

Experimental Models for Brain Tumor ......................................56

Neurobiology: Cell Migration and Dispersal ..................................59

Neurobiology: Progenitor Cells ............................................62

Radiation Biology .................................................... . .66

Treatment .............................................................69

Specific Tumors:

Extraaxial Tumors ................................................77

Intraaxial Tumors .................................................80

Metastatic Tumors of the Brain ......................................82

Pediatric Tumors .................................................84

Brain Tumor Progress Review Group Roster .....................................91

Brain Tumor Roundtable Roster ...............................................92
About the Brain Tumor Progress Review Group
About the Brain Tumor Progress Review Group 

The National Cancer Institute (NCI) supports basic, clinical, and population-based 

research to identify and study the causes, biology, prevention, early detection, and treatment of 

cancer, while the National Institute of Neurological Disorders and Stroke (NINDS) is the 

Nation’s leading supporter of biomedical research on disorders of the brain and nervous system. 

Through years of dedicated research, researchers supported by both Institutes have amassed a 

significant knowledge base about brain tumors, and this knowledge, coupled with new 

technologies, is providing a wealth of new scientific opportunities. At the same time, increasing 

research needs and scientific opportunities require that the Institutes determine the best uses for 

their resources. It is necessary to identify clear scientific priorities, both to provide guidance for 

the scientific community and to create a benchmark against which progress can be measured. 

Progress Review Groups (PRGs) were originally established to assist the NCI in assessing 

the state of knowledge and identifying scientific opportunities and needs within its large, sitespecific research programs. PRGs fit within the NCI’s overall planning framework, which 

embraces the use of expert panels and includes the establishment of Working Groups, which are 

specifically focused on aspects of scientific discovery and technology, as well as more broadly 

focused Program Review Groups. The Brain Tumor Progress Review Group (BT-PRG) was the 

first PRG to be jointly established between NCI and another NIH Institute, in recognition of the 

importance of brain tumor research to both Institutes. 

CHARGE TO THE PRG 

The BT-PRG was charged with assisting NCI and NINDS in addressing the two 

Institutes’ brain tumor research programs. PRG members were asked to take a broad view in 

identifying and prioritizing unmet scientific needs and opportunities that are critical to the 

advancement of the research field. The BT-PRG was specifically charged with the following: 

1. Identify and prioritize scientific research opportunities and needs, and the scientific 

resources needed to address them, to advance medical progress. 

2. Compare and contrast these priorities with an NCI-prepared analysis of its cancer 

research portfolio. 

3. Develop a research plan of action that addresses unmet opportunities and needs. 

4. Prepare a written report describing the PRG’s findings and recommendations for 

deliberation by the Advisory Committee to the Director (ACD) of NCI. 

This report is the final product of the Brain Tumor PRG’s (BT-PRG) efforts and 

deliberations. This report describes the group’s findings and recommendations for advancing 

brain tumor-related research. The following section details the process used in producing this and 

other PRG reports. 

About the Brain Tumor Progress Review Group 1 
THE PRG PROCESS 

The BT-PRG members were prominent scientists, clinicians, consumer advocates, and 

industry representatives from the U.S. and Canada who together represented the full spectrum of 

scientific expertise required to make comprehensive recommendations for the NCI’s and 

NINDS’s brain tumor research agenda. Members were also selected for their ability to take a 

broad view in identifying and prioritizing scientific needs and opportunities that are critical to 

advancing the field of cancer research. 

In February 2000, the PRG Leadership finalized an agenda and process for the PRG 

Planning Meeting. At the Planning Meeting, participants were identified to take part in a 

subsequent Roundtable meeting. Topics were identified for Roundtable breakout sessions to 

which those participants were ultimately be assigned and for which the PRG members served as 

co-chairs. 

The Brain Tumor PRG Roundtable Meeting (July 2000) brought together approximately 

125 leading members of the cancer research and advocacy communities, representing diverse 

institutions and scientific disciplines. These experts met in an open forum in which they 

formulated key scientific questions and priorities for the next 5–10 years of brain tumor research. 

NCI and NINDS provided the PRG Roundtable with extensive information about their research 

programs for use in their review. The research priorities and resource needs that the Roundtable 

identified in the course of their deliberations are outlined in this report. 

DEVELOPMENT OF THE PRG REPORT 

After the Roundtable Meeting, an intermediate draft report was prepared, multiple 

iterations of which were reviewed by the PRG Leadership and PRG Members. Upon completion 

of the final draft, the report was submitted for deliberation and acceptance by the NCI Advisory 

Committee to the Director and the NINDS Council. The report will be widely disseminated and 

integrated into each Institute’s planning activities. In Spring 2001, the PRG will meet with the 

NCI and NINDS Director to discuss the Institutes’ response to the report. 

PRG reports on breast, prostate, and colorectal cancer are available on line at 

osp.nci.nih.gov/Prg_assess. Other PRG reports currently in development or being planned 

include reports on pancreatic cancer; leukemia, lymphoma, and myeloma; gynecologic cancers; 

kidney and bladder cancer; stomach and esophageal cancers; liver and bile duct cancers; and skin 

cancer. 

2 Report of the Brain Tumor Progress Review Group 
Report of the Brain Tumor Progress Review Group
Report of the Brain Tumor Progress Review Group

INTRODUCTION 

Brain tumors represent a unique challenge in 

that they affect the organ that is the essence 

of the “self.” Furthermore, because each area 

of the brain serves a different but vital 

function, the therapy that is most effective 

for other cancers—surgical removal of either 

the entire organ or the tumor with a generous 

surround of normal tissue—cannot be used 

to cure brain tumors. Unfortunately, most 

brain tumors are relatively insensitive to 

other cancer treatment, including radiation 

and chemotherapy. 

Coupled with the difficulty in treating brain 

tumors is the unique biology of the brain: 

• Brain tumors occur in an organ that is 

enclosed in a bony canal that allows little 

room for growth of the tumor without 

compressing and damaging normal 

brain. 

• Many brain tumors extensively invade 

normally functioning brain, making 

complete surgical removal impossible. 

• In their early stages, brain tumors are 

protected behind a blood-brain barrier; 

even when this barrier is disrupted in the 

bulk of the tumor, infiltrating tumor cells 

at the growing edge remain protected. 

• Disruption of the blood-brain barrier 

leads to edema, which the brain tolerates 

poorly because of the limited intracranial 

space and the lack of lymphatics to rid 

itself of the products of edema and other 

debris. 

• The brain itself is rich in expressed 

genes and therefore is a fertile field for 

the growth of both primary tumors and 

metastases. 

• The brain and brain tumors appear to be 

less susceptible to attack by the immune 

system than are tumors in other organs. 

Even the term brain tumor, which suggests a 

single type of tumor, can be misleading. 

There are a bewildering variety of central 

nervous system tumors; the World Health 

Organization lists 126. Many of these 

tumors are not, strictly speaking, in the brain 

but arise from structures intimately 

associated with that organ, such as tumors of 

the covering membranes (meningiomas) and 

adjacent cranial and paraspinal nerves 

(schwannomas). Brain tumors range from 

benign (most meningiomas) to highly 

aggressive (glioblastomas). They affect both 

adults and children (although the 

distribution of tumors varies) and are often 

highly resistant to treatment. 

The term brain cancer is also misleading. 

Most cancers that arise elsewhere in the 

body cause damage by metastasizing to 

other organs (including the brain). Primary 

brain tumors, however, rarely metastasize, 

although they may widely infiltrate the 

nervous system. Conversely, many cancers 

metastasize to the brain, making metastatic 

brain tumors much more common than 

primary brain tumors. 

Throughout this document, the term brain 

tumor is used to refer to all tumors that grow 

inside the skull. The issues discussed in this 

document, however, also extend to tumors 

growing within the spinal canal. 

STRUCTURE AND PROCESS OF THE 

PRG MEETING 

For the reasons described in the introduction 

to this report, the Brain Tumor Progress 

Review Group (BT-PRG) required input 

from participants with much more diverse 

expertise than was needed in previous 

PRGs. In addition to experts on cancer 

biology and genetics, the BT-PRG required 

Report of the Brain Tumor Progress Review Group 3 
expertise in neurobiology, including areas 

such as progenitor cells, cellular migration, 

and blood-brain barrier function. Clinically, 

expertise was required from both oncology 

and the clinical neurosciences, including 

neurosurgery and neurology. In addition, to 

ensure inclusion of the wide diversity of 

brain tumors, breakout sessions were held 

not only for those topics that apply to all 

solid tumors, including brain tumors, but 

also (different from other PRGs) for specific 

types of brain tumors (i.e., intraaxial tumors, 

extraaxial tumors, pediatric tumors, and 

metastases). A total of 16 breakout groups 

were therefore convened (see box). Each 

participant attended three breakout sessions. 

The participants in each of these 16 breakout 

sessions were asked to identify three 

important research priorities in their 

assigned areas. It was recognized that it 

might not be possible to place all of the 

research priorities formulated by the groups 

into an overall hierarchy. Although all of the 

priorities included in the appendices are 

important and meritorious, some arose in 

multiple breakout sessions and therefore 

appear to be of overarching importance. This 

report delineates those priorities considered 

by the BT-PRG to be overarching. The 

appendix contains the full reports of the 

individual breakout sessions and their 

priorities. 

This report is divided into two sections. 

Section I, “Scientific Priorities,” describes 

the overarching priorities in both the basic 

and the clinical sciences. These scientific 

research priorities are hypothesis driven. To 

meet them will require the scientific 

resources described in Section II. The 

resource priorities in Section II can be 

considered as hypothesis generating in that 

their development will generate hypotheses 

for further research. 

STRUCTURE OF THE BT-PRG BREAKOUT GROUPS 

Basic Biology Clinical Biology Specific Tumors 

• Models 

• Cancer Biology and 

Etiology 

• Neurobiology: 

Progenitor Cells 

• Neurobiology: 

Migration and 

Trafficking 

• Cancer Genetics 

• Tumor Immunology 

• Detection, Diagnosis, 

and Prognosis 

• Epidemiology, 

Prevention, and 

Outcomes 

• Imaging 

• Radiation Biology 

• Therapeutic Targeting: 

Blood-Brain Barrier, 

Gene Therapy, and 

Vascular Biology 

• Treatment 

• Extraaxial Tumors 

• Intraaxial Tumors 

• Pediatric Tumors 

• Metastases 

4 Report of the Brain Tumor Progress Review Group 
SECTION I: SCIENTIFIC PRIORITIES 

Three separate sets of breakout sessions 

addressed the scientific priorities. One set 

was devoted to fundamental biology and 

included sessions on models, neurobiology 

of progenitor cells and of cellular migration 

and dispersal, cancer biology, 

immunobiology, and cancer genetics. 

Another set of sessions was related to 

clinical issues, ranging from detection and 

diagnosis to treatment and outcomes. A third 

set was devoted to specific tumors. Several 

overarching scientific priorities emerged 

from all of these sessions and are described 

here. 

Basic Biology 

Brain tumors are phenotypically and 

genotypically heterogeneous. Significant 

gaps exist in current understanding of the 

molecular pathways involved in the genesis, 

progression, and biological and clinical 

behavior of brain tumors. Brain tumors are 

unique among human cancers because of 

their complex interaction with the brain 

itself, which greatly complicates the use of 

existing therapies as well as the 

development of novel ones. 

A cardinal feature of the most common 

malignant brain tumors—their diffuse 

infiltration into the surrounding 

brain—presents substantial barriers to the 

effective delivery of therapeutic agents and 

increases the possibility of therapeutic 

toxicity to a vital organ whose function 

greatly affects the patient’s quality of life. 

Other obstacles to effective therapy include 

the blood-brain barrier and the difficulties it 

creates for therapeutic delivery, as well as 

the relative lack of information on the 

unique immunological aspects of brain 

tumors and the cerebral environment. 

The biology of brain tumors is distinct from 

that of many other human tumors. Although 

tumors are named as though their lineage 

were understood (e.g., astrocytoma from 

astrocytes), the cells of origin for most 

human brain tumors remain enigmatic, 

complicating the interpretation of data that 

require a comparison between brain tumor 

cells and their “normal” counterparts. 

Highlighting these issues are childhood 

brain tumors, especially primitive 

neuroectodermal tumors that arise during 

brain development. Insights into the normal 

and aberrant regulation of 

neurodevelopmental genes may be 

significant in understanding the etiology of 

both childhood and adult brain tumors. 

Likewise, elucidating the genetic alterations 

in brain tumors may yield new insights into 

brain development. Achieving significant 

advances in the diagnosis, prognosis, 

therapy, and prevention of brain tumors 

requires unraveling and understanding many 

aspects of the cellular and molecular biology 

of brain tumors and their interactions with 

normal brain elements. These advances must 

proceed along a number of different fronts 

and will require the interaction of several 

disciplines in order to achieve the greatest 

chance of success (see “Communication” in 

Section II of this report). 

Many of the priorities generated by the 

breakout sessions of the BT-PRG 

overlapped, particularly those concerning 

needed resources (see Section II). The 

highest scientific priorities in basic biology 

identified by such overlap are as follows: 

• Understand the complex biology of brain 

tumors, both primary and metastatic, and 

their interaction with normal brain 

elements as they relate to oncogenesis, 

progression, tumor cell dispersal, and 

heterogeneity. 

Report of the Brain Tumor Progress Review Group 5 
— Define the genetic changes and 

molecular pathways involved in 

brain tumor initiation and 

maintenance. 

— Characterize the interactions of brain 

tumor cells with the normal brain. 

• Provide a detailed molecular 

classification of the cells of origin for 

distinct tumor types and define their 

lineage associations, as well as the signal 

transduction pathways that regulate cell 

fate and the mechanisms by which the 

local environment of the brain influences 

cell migration and differentiation. 

• Understand genotypic influences on 

phenotypic behavior, tumor type, age at 

onset, anatomical position, cell of origin, 

and cellular biology. 

• Isolate the genes that predispose to 

human brain tumors and understand their 

relationship to the genes that regulate 

normal development. 

• Identify the genes that regulate patients’ 

responses to chemotherapy and 

radiotherapy and those that mediate 

tumor chemoresistance and 

radioresistance. 

• Characterize both central nervous system 

and systemic immune responses in 

patients with brain tumors. 

• Understand the blood-brain barrier and 

its regulation. 

• Understand the mechanisms underlying 

the spread and establishment of 

metastases in the central nervous system. 

Epidemiology 

Little is known about the epidemiology of 

brain tumors. Germ line mutations (familial 

brain tumor syndromes) account for no more 

than 7% of patients. The only unequivocally 

established risk factors for nonfamilial brain 

tumors—therapeutic irradiation to the brain 

and chronic immunosuppression (e.g., 

AIDS)—are also infrequent causes of brain 

tumors. Other suggested etiologies, such as 

nonionizing radiation (e.g., from cellular 

telephones or high-tension wires), viral 

agents, household chemicals, or foods, have 

not been established as causal. In addition, 

little is known about the interaction of 

genetic factors and environmental toxins in 

the genesis of brain tumors. 

Because identification of the risk factors for 

brain tumors may aid prevention and suggest 

effective treatments, high-quality 

epidemiological studies are extremely 

important. Factors that inhibit 

epidemiological studies include the 

relatively small number of patients affected 

by brain tumors and the large number of 

histopathological types of these tumors. 

These factors complicate the design of 

research protocols and limit the statistical 

power of the data collected. In addition, 

existing tumor registries are neither linked 

nor structured to facilitate the collection of 

large numbers of samples for meaningful 

epidemiological research. Important 

epidemiological scientific priorities, 

therefore, include the following: 

• Support the linking of existing databases 

to provide larger numbers of samples for 

epidemiological studies. 

• Expand and enhance databases to 

include all primary brain and spinal 

tumors—malignant and nonmalignant, 

adult and pediatric—and to have the 

flexibility to accommodate new 

histological and molecular classifications 

of tumors. 

• Develop epidemiological studies of 

patients’ susceptibility to the toxic 

effects of current treatment modalities 

and investigate risk and protective 

factors with study designs that 

incorporate biological measures. 

• Use validated animal models (see 

“Models,” Section II) to study the 

6 Report of the Brain Tumor Progress Review Group 
potential causal factors of brain tumors 

and of treatment-induced neurotoxicity. 

Detection and Diagnosis 

Because brain tumors are an extraordinarily 

heterogeneous group of lesions, accurate 

diagnosis is essential to proper management. 

Current imaging techniques provide a 

sensitive means for delineating the 

anatomical features of brain tumors but have 

not provided an effective means for early 

detection. Early detection could also be 

complicated by the ethical problems created 

by presymptomatic diagnosis of tumors for 

which there may not be effective treatment, 

and in an organ whose proper function is 

essential to quality of life. Nonetheless, early 

detection of brain neoplasms, particularly in 

the pediatric population, where these lesions 

are often treatable, could be facilitated by 

appropriate education of pediatricians, 

parents, school officials, and other 

caregivers. 

The diagnosis of brain tumors is currently 

based on histological examination of brain 

tumor tissues after radiological 

characterization and surgical biopsy. These 

approaches are successful in classifying and 

grading most cases, but in many situations 

they do not allow accurate prediction of 

therapeutic responses or of prognosis. The 

situation may be further complicated by the 

small size of some diagnostic biopsy 

samples. There is therefore a critical need to 

improve the diagnosis of brain tumors in 

order both to improve current therapeutic 

management strategies and to form a basis 

for the evaluation of novel approaches. 

The ability to characterize tumors 

comprehensively at the molecular level 

raises the possibility that diagnosis could be 

based on molecular profiling, either alone or 

with histological examination, rather than on 

histological phenotype alone. Once such 

techniques become possible and practical, 

molecular profiling could be accomplished 

by tissue analysis or imaging. In the future, 

molecular markers could also form the basis 

for screening at-risk individuals or 

populations. In light of such possibilities, the 

following priorities in the detection and 

diagnosis of brain tumors were identified: 

• Develop a molecular- and imaging-based 

classification scheme for brain tumors 

that can be used to predict tumor 

behavior and to guide treatment 

decisions more accurately and 

objectively than is possible with current 

histopathological methods. 

• Develop techniques that can reliably 

detect brain injury related to tumor or 

treatment and use such techniques to 

assess the efficacy of neuroprotective 

interventions. 

Treatment 

Treatment options for patients with brain 

tumors have been limited and, for most 

types of tumors, have provided only modest 

benefits. Some of the likely reasons for these 

limitations (see “Introduction”) include the 

unique structural and physiological aspects 

of the central nervous system, especially its 

vulnerability to damage from many therapies 

as well as from neoplastic processes 

themselves. Research in the treatment of 

brain tumors has been hampered by the lack 

of clinically predictive model systems; by a 

minimal understanding, until quite recently, 

of fundamental tumor biology; and by a 

narrow range of available therapeutic agents 

for testing that have had little expected 

specificity for brain tumors. The major 

challenge for the future is to develop more 

effective techniques to treat brain tumors 

without damaging the brain. 

Report of the Brain Tumor Progress Review Group 7 
Marked progress is currently being made in 

dissecting the molecular mechanisms of 

neoplasia in the brain and elsewhere. These 

advances are enabling the rapid 

identification of relevant molecular targets, 

and the result is a vast array of potential 

therapeutic approaches and agents in the 

development pipeline. At the same time, 

advances in neuroimaging are raising the 

tantalizing possibility of clinically assessing 

the capacity of an agent to alter its intended 

target. It therefore seems reasonable to 

expect an improved rate of success in 

research on the treatment of brain tumors. 

Because the special characteristics of these 

tumors will continue to present problems 

and challenges, however, the following 

priorities were identified: 

• Facilitate the development of novel 

therapeutic agents and approaches for 

adult and pediatric brain tumors. These 

approaches should include, but not be 

limited to, chemotherapeutic, 

immunologic, antiangiogenic, genetic, 

and viral agents. 

• Increase knowledge about the 

mechanisms of existing therapies for 

both adult and pediatric brain tumors. 

• Improve the therapeutic index of new 

agents that are specifically relevant to 

the central nervous system. 

• Enhance the therapeutic ratio for 

radiation therapy for brain tumors. 

(Overcome radioresistance of primary 

brain tumors; overcome normal tissue 

toxicity such as necrosis/edema and 

functional deficits.) 

• Develop novel drug targeting systems 

that enhance the uptake by brain tumors 

of small- and large-molecule diagnostic 

and therapeutic agents. 

• Develop clinical consortia for 

immunotherapy that are similar to those 

for radiation and chemotherapy. 

• Develop therapies that are less toxic than 

existing therapies to both the mature and 

the immature nervous system. 

Outcomes 

Traditional outcome measurements used in 

brain tumor studies have included overall 

and recurrence-free patient survival and, in 

some instances, radiological response to 

therapy. Such measurements, however, 

largely ignore crucial issues relating to 

quality of life and biological endpoints of 

response. These issues are of particular 

importance in tumors for which effective 

therapies may not exist and in pediatric 

tumors, for which effective tumor control 

may be associated with significant long-term 

morbidity. For these reasons, there is an 

immediate and crucial need for better 

measurement tools and surrogate markers to 

assess patient quality of life and tumor 

response to therapy. Such outcome markers 

would facilitate the assessment of 

neurotoxicity, thereby providing an 

opportunity to discard potentially neurotoxic 

therapies sooner. They would also facilitate 

more accurate assessment of therapeutic 

response, thereby allowing effective 

therapies to be continued while ineffective 

therapies are discontinued. The following 

priorities were therefore identified: 

• Improve techniques for measurement of 

quality of life and include such 

measurements in all clinical trials of 

brain tumor. 

• Refine the ability to detect response to 

existing therapies, such as radiation, and 

to novel treatments, using surrogate 

markers measured either by imaging or 

in biological fluids (e.g., serum or 

cerebrospinal fluid). 

• Establish clinical and imaging markers 

of neurotoxicity from existing therapies, 

8 Report of the Brain Tumor Progress Review Group 
such as radiation, and from novel 

treatments. 

• Extend the use of such markers to 

preclinical evaluations in animal models. 

Specific Tumors 

Recognizing the remarkable diversity of 

human brain tumors and the distinct clinical 

questions associated with different tumor 

types, the PRG members were concerned 

that most of the general scientific sessions 

would concentrate on the more common 

tumors, such as malignant gliomas and 

medulloblastomas, to the exclusion of other 

brain tumor types. To address the possibility 

that research priorities might relate to 

different types of brain tumors, the PRG 

convened four special breakout sessions to 

focus on particular groups of brain tumors: 

pediatric brain tumors, intraaxial brain 

tumors (excluding malignant gliomas and 

medulloblastomas), extraaxial brain tumors, 

and metastases to the brain. These four 

special breakout sessions met after the 12 

general scientific sessions had adjourned. 

The special sessions included attendees from 

the earlier, general discussions, thereby 

allowing important issues from the general 

sessions to be applied to discussions of the 

specific tumor groups. 

Remarkably, the research priorities and 

needed resources identified by these special 

groups echoed those of the general sessions, 

although some different emphases were 

placed according to tumor type: 

• The session on pediatric brain tumors 

emphasized clinical problems such as 

the need to study long-term outcomes for 

survivors of brain tumors, to investigate 

the impact of therapies on the 

developing brain, and to focus on some 

of the rarer, more primitive tumors 

occurring in children. 

• The group addressing intraaxial brain 

tumors highlighted issues relating to 

low-grade gliomas, primary central 

nervous system lymphomas, and germ 

cell tumors. 

• The session on extraaxial brain tumors 

emphasized the need for studies that 

incorporate careful long-term follow-up 

for these often slowly growing lesions. 

• The group discussing metastatic tumors 

of the brain made the unique 

recommendation to convene a PRG 

devoted to the biology of metastasis. 

The specific priorities from these sessions 

are detailed in the individual reports in 

Appendix A. 

SECTION II: RESOURCE PRIORITIES 

Although the scientific priorities set forth by 

the BT-PRG varied considerably across the 

different areas of scientific and clinical 

investigation, the resources required to 

accomplish those priorities were remarkably 

concordant. Indeed, nearly all of the five 

resource priorities listed below were deemed 

essential by most of the participants: 

1. Models 

2. Tissue banks and databases 

3. Genomics and high-throughput 

screening 

4. Communication 

5. Training 

These resources can be viewed as hypothesis 

generating because they will provide the 

information and abilities to accomplish the 

scientific and clinical priorities listed in 

Section I. The creation of these resources is 

deemed essential in order to develop new, 

effective therapies for brain tumors. 

Report of the Brain Tumor Progress Review Group 9 
Models 

Models are central to making the transition 

from developing scientific concepts to 

understanding human tumors within the 

context of the tissues that they affect. 

Models may be used for therapeutic screens, 

in preclinical trials, or to study the basic 

biology of tumors. However, because 

currently available cellular, tissue, and 

animal models do not accurately represent 

the biology of human brain tumors, it is vital 

to: 

• Develop tissue and cell culture systems 

that replicate the biology of human brain 

tumors. 

• Create genetically and behaviorally 

accurate models for brain tumors in mice 

and other animals. 

• Generate tissue-based, imaging, and 

genomic methods to validate and 

compare animal models with their 

human counterparts. 

• Improve the availability of the reagents 

needed to create new animal models of 

brain tumors, the sophisticated 

technologies used to evaluate and 

validate those models, and the animal 

models themselves. 

To accomplish these priorities, a mechanism 

must be created to support the development 

and validation of model systems that more 

accurately reflect the biology of brain 

neoplasms. Although the National Cancer 

Institute (NCI) Mouse Models for Human 

Cancer Consortium (MMHCC) has been 

established to fund the development of 

mouse cancer models, additional mouse 

models of the various brain tumors that are 

not addressed through the MMHCC, as well 

as models in other animals, remain high 

priorities. 

Tissue Banks and Databases 

Addressing the complex biology of brain 

tumors requires innovative tumor banking 

and characterization facilities with relevant 

and appropriate clinical and radiological 

databases. Tissue banks linked to clinical 

databases are also vital for translating 

research discoveries into clinically relevant 

information. Because current tissue banks 

are typically institution based, they are 

limited in scope and amount of available 

specimens. These banks also process tissues 

in different ways, and their specimens are 

usually not sufficiently annotated with 

clinical and radiological information. 

Because of the rarity of many brain tumor 

types, including both adult and pediatric 

neoplasms, there is a great need for 

organized, interinstitutional approaches to 

banking and data management of both adult 

and pediatric neoplasms. 

An effective tissue bank or database must do 

the following: 

• Collect and bank tissue, blood, 

cerebrospinal fluid, and (when available) 

normal brain from patients with all 

varieties of brain tumors. In particular, 

attention should be paid to banking 

pediatric tumors; rarer intraaxial tumors, 

such as low-grade gliomas and 

lymphomas; tumors that follow long 

clinical courses, such as meningiomas; 

and metastases, when tissue from the 

primary tumor is also available. 

Specialized banks should also focus on 

acquiring clinical and radiological 

information and tissues from distinct 

populations, such as patients with 

neurofibromatosis 2, who provide 

unique opportunities to follow the 

natural history of particular tumors. 

Public and professional educational 

efforts will be required to ensure that 

10 Report of the Brain Tumor Progress Review Group 
both common and rare brain tumors are 

submitted to the banks. In this regard, a 

challenge will be to alter the sociology 

of data sharing in order to make a 

concerted shift to a shared, distributed 

system. 

• Maintain a comprehensive database of 

relevant clinical and demographic, 

pathologic, biologic, and therapeutic 

information on all patients whose tissue 

is banked. Develop links to population 

databases to enhance potential 

etiological and other epidemiological 

studies. 

• Involve multidisciplinary participation of 

surgeons, pathologists, scientists, and 

other professionals, including 

neurooncologists, to ensure reliable and 

consistent tissue processing. 

• Provide mechanisms to ensure access, on 

a competitive and open basis, by 

researchers to the material and data in 

the bank. 

• Employ approved and ethical 

methodologies to protect patient 

confidentiality and ensure appropriate 

patient consent. 

• Feature local and regional facilities and 

facilitate effective communication and 

collaboration among centers. 

• Be supported by ongoing funding, 

potentially for longer than 5-year 

periods, to facilitate study of tumors with 

long clinical courses, such as 

meningiomas. 

Genomics and High-Throughput 

Screening 

The explosion of information in genomics, 

together with the promise of similar 

advances on the near horizon in proteomics, 

raise the need for technologies that allow 

high-throughput screens of brain tumors and 

related specimens (e.g., other tissues from 

patients with brain tumors). Such highthroughput screens would allow large 

amounts of information to be gleaned 

quickly and would facilitate further 

translational research toward more tailored 

therapeutic approaches. These screens can 

occur at the tissue level ex vivo or, in the 

future, at the molecular neuroimaging level 

in vivo. For such large-scale approaches to 

be functional, considerable emphasis will 

need to be placed on bioinformatics support. 

The need for high-throughput screening 

technologies was identified by a number of 

the different breakout sessions; the highest 

priorities were the following: 

• Develop high-throughput laboratory 

approaches to understand gene function 

and to identify the targets and pathways 

that are critical to brain tumor biology. 

• Develop high-throughput laboratory 

approaches to identify the genes and 

genetic variations that underlie tumor 

resistance to chemotherapy and radiation 

therapy, as well as the allelic variations 

that influence responses to therapy in 

individual patients. 

• Develop high-throughput laboratory 

approaches to identify antigens that may 

be used to further understanding of the 

immunological features of brain tumors 

and to develop novel immunological 

therapies. 

• Develop high-throughput neuroimaging 

approaches for the in vivo 

characterization of the molecular 

features of tumors and the surrounding 

brain that could monitor and influence 

therapies. 

• Develop the bioinformatics support 

necessary for rapid and accurate analysis 

of data generated via these highthroughput approaches. 

• Establish a consortium of brain tumor 

modeling laboratories for the purpose of 

testing novel therapies. 

Report of the Brain Tumor Progress Review Group 11 
• Allocate resources for the generation of 

cDNA microarrays based on the mouse 

equivalent of the human sequences 

identified through the Brain Tumor 

Genome Anatomy Project (BT-GAP). 

• Create a mechanism to ensure affordable 

access to these reagents and models. 

Communication 

The PRG Roundtable meeting provided a 

unique opportunity for scientists from 

different disciplines—including cancer 

biology and genetics, neurobiology, 

immunology, and radiation biology—to 

meet and discuss brain tumor biology. These 

stimulating interactions highlighted the 

potential for novel insights arising from such 

interdisciplinary interactions. A central goal 

that emerged from these discussions was the 

need for further communication among these 

various disciplines on the subject of brain 

tumor biology. Such enhanced 

communication would in turn lead to 

interdisciplinary collaborations that would 

approach problems in brain tumor research 

from a unified, and therefore novel, 

perspective. 

It was recognized that one reason for the 

relative lack of such communication and 

collaboration among disciplines has been the 

historically different funding and oversight 

mechanisms that have supported such 

research. For example, neurobiology 

research is largely funded through the 

National Institute of Neurological Disorders 

and Stroke (NINDS), whereas cancer 

biology and immunology research is 

generally funded by NCI and other agencies. 

Recent attempts to bring together NCI and 

NINDS to address questions in brain tumor 

research—the BT-PRG, the BT-GAP, and 

the establishment of a combined NCININDS Neurooncology Branch—have been 

widely applauded and further 

interinstitutional interactions strongly 

encouraged. The possible extension of such 

interactions to the grants review process was 

also deemed an important area for 

discussion. 

Because the Center for Scientific Review 

(CSR) reviews most unsolicited brain tumor 

grant applications, the brain tumor research 

community believes that better coordination 

among the institutes and CSR is needed. 

Improved communication could prevent 

brain tumor biology from “falling between 

the cracks” among the various review groups 

that may have relatively few brain tumor 

biologists. It is anticipated that coordinated 

efforts by NINDS, NCI, and CSR on the 

referral, review, and funding of brain tumor 

research applications would facilitate the 

implementation of the national plan for brain 

tumor research. 

Goals for improved communication extend 

to clinical problems as well. There is clearly 

a need for increased dissemination of 

information to patients, as well as to 

clinicians outside of neurooncology centers, 

with regard to the variety of available 

treatment options. The relatively low 

percentage of patients with adult malignant 

gliomas who are enrolled in clinical trials 

may reflect an inadequate knowledge of 

treatment options on the part of both patients 

and physicians. This area of need represents 

an ideal opportunity for patient advocacy 

groups to collaborate with physicians to 

develop strategies to educate patients and 

clinicians about treatment options, including 

clinical trials, as well as about the 

specialized expertise that is available at 

neurooncology centers. For these reasons, 

the following priorities were identified: 

• Establish a set of interactive meetings 

involving scientists from different 

biological disciplines (cancer biologists 

12 Report of the Brain Tumor Progress Review Group 
and geneticists, neurobiologists, 

immunologists, and radiation biologists) 

that focus specifically on important 

issues in brain tumor biology. 

• Facilitate collaborations among different 

disciplines by encouraging 

interdisciplinary grant applications in 

brain tumor biology and etiology. 

• Continue to develop combined programs 

in brain tumor research from NCI and 

NINDS and explore the possibility of 

revisions in the grant review process for 

brain tumor research. 

• Encourage coordinated activities by 

advocacy groups toward further 

education of patients and clinicians 

about available treatment options for 

brain tumors. 

Training 

Achieving the goals for brain tumor research 

outlined in this report requires an adequately 

sized and well-trained scientific and clinical 

work force specializing in brain tumor 

research. Unfortunately, there is a dearth of 

basic scientists working in the field of brain 

tumors, which lacks sufficient numbers of 

clinicians who are cross-trained in brain 

tumor biology and scientists who are aware 

of the problems driving clinical 

neurooncology research. As is the case for 

biomedical science in general, there exists a 

true crisis caused by the small number of 

clinician-investigators now entering 

academic medicine. This issue has been 

discussed elsewhere and will not be 

recapitulated here, but its importance should 

not be underestimated. High priorities for 

brain tumor research are therefore as 

follows: 

• Enhance training opportunities and 

support: 

— Encourage funding for 

interdisciplinary and translational 

research. 

— Recruit new talent and sustain 

proven talent in the field of brain 

tumor research. 

• Create innovative public and private 

programs to stimulate promising young 

investigators to choose a career in 

clinical or laboratory brain tumor 

research through, for example, tuition 

loan payback or forgiveness and 

fellowships. 

• Develop a joint NCI-NINDS campaign 

to encourage students to pursue 

interdisciplinary careers in the field of 

brain tumor research. 

• Develop at NIH a model for a joint NCININDS interdisciplinary training 

program in neurooncology at both the 

basic science and the clinical level. This 

program might include not only training 

at NIH for 2–3 years, but also additional 

support for the first 3 years of the 

individual’s career as an independent 

investigator. 

CONCLUSION 

Although not among the most common of 

neoplasms, brain tumors are among the most 

devastating. Mental impairment, seizures, 

and paralysis afflict the very core of the 

person and have a demoralizing effect on 

loved ones. Added to these burdens is the 

knowledge that, for most brain tumors, 

adequate treatment is not available and the 

likelihood for long-term survival is poor. In 

children, even if they do survive, the 

devastating impact of disease and treatment 

often leaves permanent neurological 

damage. 

Recent advances in the clinic, as well as in 

neuroscience and cancer biology, make the 

present an opportune time for a major attack 

Report of the Brain Tumor Progress Review Group 13 
on brain tumors. As indicated in this report, 

progress has been made in the basic 

understanding of many aspects of brain 

tumor biology. These advances promise to 

provide new targets for therapies and more 

rational ways of delivering these novel 

therapies. In the clinic, new techniques in 

surgery and radiation therapy are just 

beginning to be exploited in the treatment of 

brain tumors. Other innovative approaches, 

such as gene and immunological therapies, 

are still in their infancy but represent 

substantial hopes for the future. Preventive 

factors identified in recent epidemiological 

studies, if replicated and understood at the 

biological level, may lead to intervention 

strategies. 

The priorities outlined in this report provide 

a framework to guide progress in the field of 

brain tumor research. A concerted, 

interdisciplinary, and timely approach to 

addressing these priorities will allow the 

development of new diagnostic and 

therapeutic techniques that may ameliorate 

and, it is hoped, eventually cure brain 

tumors. 

14 Report of the Brain Tumor Progress Review Group 
Appendix: Full Reports of the Brain Tumor Progress Review 

Group Roundtable Breakout Sessions 
Cancer Biology and Etiology 

Co-chairs: Francis Ali-Osman, D.Sc., and Tom Curran, Ph.D. 

Participants: 

Michael Berens 

Mitchel Berger 

Webster Cavenee 

Rolando Del Maestro 

Ronald A. DePinho 

Richard A. Fishel 

Henry Friedman 

Candece Gladson 

Peter T. C. Ho 

Susan Hockfield 

Mark A. Israel 

C. David James 

William G. Kaelin 

Robert L. Martuza 

Christina A. Meyers 

Jasti Rao 

Sandra Rempel 

James Rutka 

Richard Vallee 

Jeannine Walston 

Albert Wong 

Roy S. Wu 

W. K. Alfred Yung 

STATEMENT OF THE PROBLEM 

• Brain tumors are highly heterogeneous, 

both phenotypically and genotypically. 

• Significant gaps exist in our knowledge 

and understanding of the genes, genetic 

changes, and pathways involved in the 

genesis, progression, and biological 

and clinical behavior of brain tumors. 

• There is currently an inadequate 

understanding of brain tumor biology, 

particularly as it relates to the complex 

environment of the brain. 

• The achievement of significant 

advances in diagnosis, prognosis, 

therapy, and prevention of brain tumors 

will require unraveling and 

understanding the cellular and 

molecular biology of brain tumors and 

their interactions with normal brain. 

CHALLENGES AND QUESTIONS 

• What are the genetic changes and 

pathways of oncogenesis and 

progression that account for the 

heterogeneity of brain tumors, and how 

can these be studied? 

• Which genes, genetic changes, and 

pathways are important to the 

initiation, maintenance, and 

progression of brain tumors? 

• Are the genetic changes and pathways 

that are required for initiation the same 

as those required for maintenance of 

the neoplastic phenotype and its 

biological behavior? 

• What model systems and approaches 

are required to advance our study of 

these multigenetic changes and 

pathways? 

• What are the interactions between the 

brain tumor and the normal brain? 

• How do tumor-brain interactions 

contribute to oncogenesis and 

metastasis in the central nervous 

system? 

• “Seed-soil” interactions: How does the 

spatial-anatomical site of the tumor 

against its specific genetic background 

determine the gene expression patterns 

and contribute to tumor heterogeneity, 

biological and clinical behavior, and 

therapeutic outcome? 

• Are there genetic changes and 

pathways that are common to different 

brain tumor subtypes? 

• What pathways, such as signaling, 

apoptosis, cell cycle, and migration, are 

involved in the response of brain 

tumors to intra- and extracellular 

stimuli such as growth factors or redox 

changes? 

Cancer Biology and Etiology 15 
• What are the stem cells and progenitor 

cells of the different brain tumor 

subtypes? 

• What model systems and approaches 

are required to advance the study of 

brain tumor biology and of the 

interactions between tumor cells and 

normal brain? 

• If the genetic changes or lesions that 

initiate cancer are different from those 

required for progression and 

maintenance, could these be targeted in 

order to develop novel therapies? 

BARRIERS 

• Interdisciplinary barriers: 

— There is poor communication and 

collaboration between researchers in 

neurobiology and those in 

neurooncology, although expertise and 

advances in each field are essential to 

advancing understanding of brain 

tumor biology. 

— Current infrastructure and systems 

do not encourage or facilitate 

interdisciplinary interaction. 

— In the current grant review process, 

interdisciplinary grants that would 

encourage collaboration are often not 

reviewed favorably because of the 

existing review criteria. 

• Tissue resource barriers: Existing 

tumor banks often do not have 

appropriate, relevant information, such 

as information on diagnosis, biological 

characteristics, natural history, and 

therapeutic outcome. The banks also 

often do not collect normal tissue or 

blood. 

• Models: There is a lack of appropriate 

in vitro and in vivo models and 

systems with which to study the 

complex biology of brain tumors. 

• Technological barriers: There is an 

inadequate application to brain tumor 

biology research of the latest 

technological advances, such as those 

in genomics and proteomics, structural 

biology, chemical biology, and highthroughput screening strategies. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Understand the complex biology of brain 

tumors and their interaction with the 

normal brain as it relates to oncogenesis, 

progression, and heterogeneity. 

• Define the multigenetic changes and 

pathways involved in oncogenesis, 

progression, and maintenance of brain 

tumors, with particular attention to 

their heterogeneity. 

• Identify the genes and pathways that 

are differentially involved in tumor 

initiation and maintenance. 

• Characterize the interactions of the 

tumor cell with normal brain 

components as determinants of 

heterogeneity, gene expression, 

biological and clinical behavior, and 

therapeutic response within the context 

of the specific anatomical sites of the 

brain in which the tumor is located. 

• Define and characterize the cells of 

origin of different brain tumor 

subtypes. 

Priority 2: 

Develop appropriate model systems for 

studying brain tumor biology that will 

allow for the following: 

• Mimic the biological complexity of the 

brain, including brain matrix 

16 Report of the Brain Tumor Progress Review Group 
• Facilitate comparative genetic studies 

in human brain tumors and animal 

brain tumor models 

• Provide an interface between tumor 

cell and stem cell biology 

• Study interactions and pathways 

between brain tumor cells and cellular 

components of normal brain 

• Study molecular, cellular, and spatial 

heterogeneity in brain tumors 

• Study the functional outcome of 

specific genetic lesions 

• Evaluate novel therapies that target 

specific genes, gene products, and 

pathways 

Priority 3: 

Develop high-throughput approaches to 

understand gene function and to identify 

the targets and pathways that are critical 

to brain tumor biology and therapy. 

RESOURCES NEEDED 

Priority 1 

• Address the complex biology of brain 

tumors requires innovative tumor 

banking and characterization facilities 

with relevant and appropriate 

databases. These facilities will enable 

the following: 

— Collect and bank tissue, blood, 

cerebrospinal fluid, and (when 

available) normal brain from patients 

with all varieties of brain tumors. 

— Maintain a comprehensive database 

of relevant clinical and demographic, 

pathological, biological, imaging, and 

therapeutic information on tumors. 

— Involve the multidisciplinary 

participation of surgeons, pathologists, 

scientists, and other professionals, 

including neurooncologists, for tissue 

processing. 

— Have mechanisms in place to 

ensure access by researchers to the 

material and data in the bank. 

— Include local (institutional) or 

regional centers and encourage 

communication and collaboration 

among centers. 

— Receive ongoing funding, 

specifically for longer than 5-year 

periods, because of the long-term 

nature of tissue banking 

• Establish a centralized molecular 

profiling (cDNA and tissue array) 

resource with a strong bioinformatics 

component to profile gene expression 

patterns and genetic abnormalities in 

different brain tumor types. Such a 

facility could be located at NCI or 

NINDS or could be extramural. 

• Develop the infrastructure and 

mechanisms to open up 

communication and collaboration 

among researchers in neuroscience, 

neurobiology, neurooncology, and 

cancer biology. Such an infrastructure 

would include: 

— Workshops and specialized 

meetings among these scientists 

— New funding mechanisms and 

grant review criteria appropriate for 

interdisciplinary research 

Priority 2: 

Targeted funding is needed for the 

development of model systems. 

Priority 3: 

Resources are needed to develop the 

following: 

• Chemical and combinatorial libraries 

and high-throughput assays to 

Cancer Biology and Etiology 17 
investigate molecular targets and 

pathways 

• Structural and computational biology 

resources 

• Functional genomics and proteomics 

• Studies of ligand (drug)-protein 

interactions 

• Targeted funding for high-throughput 

technologies 

18 Report of the Brain Tumor Progress Review Group 
Therapeutic Targeting, Blood-Brain Barrier, Gene Therapy, 

and Vascular Biology 

Co-chairs: William M. Pardridge, M.D., and Edward H. Oldfield, M.D. 

Participants: 

Keith Black 

Peter M. Black 

Ronald G. Blasberg 

E. Antonio Chiocca 

Pam Del Maestro 

Lester Drewes 

Ramon Gilberto Gonzalez 

Frederick F. Lang, Jr. 

John Mazziotta 

Sherie Morrison 

Edward A. Neuwelt 

Sam D. Rabkin 

Bruce Rosen 

Richard Youle 

STATEMENT OF THE PROBLEM 

An important problem in the treatment of 

human brain tumors is posed by the need to 

deliver therapeutic agents to specific regions 

of the brain, distributing them within and 

targeting them to brain tumors. The 

molecules that might otherwise be effective 

in diagnosis and therapy either do not cross 

the blood-brain barrier (BBB) in the brain 

adjacent to the tumor or do not cross the 

blood-tumor barrier (BTB) in adequate 

amounts. Improving our knowledge of the 

basic molecular and cellular biology of the 

brain microvasculature, which constitutes 

the BBB and BTB in vivo, could lead to 

innovative new strategies for drug targeting 

to human brain tumors. 

The magnitude of this challenge stems from 

the lack of emphasis on BBB research in 

both academic neuroscience and the 

pharmaceutical industry. Knowledge of the 

basic functions of the BBB and research on 

cerebrovascular biology lag behind those of 

neuronal or glial biology. An improved 

understanding of the brain vasculature and 

the BBB will play a crucial role in the 

development of new therapeutic and 

diagnostic approaches for the treatment of 

human brain tumors. In addition, there is a 

need for novel delivery strategies that are 

unique to the brain and that bypass the vasculature. 

At one time, the BBB was not been 

considered to present a problem in the 

diagnosis and treatment of brain tumors 

because early scans of human brain tumors 

suggested that the BTB was “leaky.” This 

leakiness is relative, however: as the size of 

the molecule increases, the rate of 

movement across the barrier decreases. 

Accordingly, antibodies that could be used 

as either diagnostic or therapeutic molecules 

do not cross the BTB in sufficient quantities 

to be effective. Anti-sense oligonucleotides, 

which could be used either to inhibit 

oncogenic signals or as anti-sense 

radiopharmaceuticals to image gene 

expression of the brain in vivo, also do not 

cross the BTB in sufficient amounts for 

activity. Gene therapies, whether of viral or 

nonviral formulations, are often too large to 

cross the BTB. 

These problems are substantially greater for 

the BBB in the brain adjacent to the tumor, 

because even small molecules do not readily 

cross the BBB, which is the site of invasion 

of glioma cells into normal brain. 

Furthermore, the expression of drug-active 

efflux transporters, which are expressed at 

the BBB and the BTB, actively efflux 

chemotherapeutics from the brain back to 

the blood and may thereby prevent 

Therapeutic Targeting 19 
significant distribution of chemotherapeutic 

agents in the brain. It is partly for these 

reasons that most of the classical 

chemotherapeutic molecules that have been 

used to treat cancer outside the central 

nervous system (CNS) are ineffective in the 

treatment of brain tumors. 

CHALLENGES AND QUESTIONS 

Chief among the challenges to be addressed 

in brain tumor research is limited knowledge 

about the basic biology of brain endothelial 

cells, about the cells of origin and the 

developmental changes in gene and protein 

expression in brain and endothelial cells, 

and about the proliferative potential, 

turnover rate, and regional differences of 

brain endothelial cells. There is also limited 

knowledge of the cell interactions among 

brain endothelial cells, tumor cells, and cells 

of hematopoietic origin. The role of 

angiogenesis in tumor development and antiangiogenesis research are important avenues 

for future studies of brain tumor therapy. 

Mechanisms for drug targeting in the brain 

involve going either “through” or “behind” 

the BBB. Modalities for drug delivery 

through the BBB entail disruption of the 

BBB, either by osmotic means or 

biochemically by the use of vasoactive 

substances such as bradykinin. The potential 

for using BBB opening to target specific 

agents to brain tumors has just begun to be 

explored. Other strategies to go through the 

BBB may entail the use of endogenous 

transport systems, including carriermediated transporters such as glucose and 

amino acid carriers; receptor-mediated 

transcytosis for insulin or transferrin; and 

active efflux transporters such as pglycoprotein. Strategies for drug delivery 

behind the BBB include intracerebral 

implantation and convection-enhanced 

distribution. There is a need to determine 

which strategies are most effective and how 

they can be improved for patients with brain 

tumors. 

Cerebral edema is a serious complication in 

many patients with brain tumors. The 

molecular and gene-related mechanisms 

underlying the formation of cerebral edema 

need to be identified. Also needed are more 

quantitative methods to measure flux or 

transfer rate constants as indicators of 

vascular permeability in patients and 

experimental animals. We also need to 

improve our understanding of how to 

reverse edema and to better understand the 

mechanisms underlying the effects of current 

therapies. 

Current in vitro models of the BBB are 

inadequate. Although brain endothelial cells 

co-cultured with astrocytes have been used 

to study the BBB, better in vitro models that 

retain the phenotype of brain endothelial 

cells will be valuable, as would an in vitro 

model of the BTB. Basic research on brain 

tumors would be facilitated by the 

development of appropriate models that 

simulate the human condition in situ. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Develop strategies for delivering both 

small and large molecules to the CNS. 

The transport of small molecules might be 

enhanced by designing drugs that have 

affinity for one of the carrier-mediated 

transporters within the BBB. Alternatively, 

drugs that inhibit the active efflux 

transporters may be useful as “co-drugs” to 

mediate the uptake of chemotherapeutic 

agents that are normally effluxed from brain 

to blood. Tumor-specific agents could be 

used with BBB disruption. Similar 

approaches might be used to develop new 

20 Report of the Brain Tumor Progress Review Group 
diagnostics for human brain tumor imaging. 

Peptide or antisense radiopharmaceuticals 

could be developed as molecular “Trojan 

horses” that bind to endogenous receptormediated transporters in the BBB and are 

transferred across the BBB by this 

mechanism. 

An important mission for the future, not 

only for brain tumors but for the field of 

neuroscience in general, is the ability to 

“image any gene in any person.” This might 

be done with antisense radiopharmaceuticals 

that are made transportable through the 

BBB. This is a “barrier” problem, because to 

be successful, an antisense molecule targeted 

at an mRNA molecule within the tumor cell 

must be transported across not only the BTB 

but also the tumor cell and organelle 

membrane “barriers.” 

Priority 2: 

Identify the genes and proteins expressed 

by the BBB and the BTB. 

BBB genomics should be considered a high 

priority. Because only very abundant BBBspecific transcripts will be detected with 

whole-brain gene microarrays, BBB 

genomics research needs to start with the 

initial isolation of brain capillaries from 

animal or human brain, both normal and 

tumor derived. Comparison of capillaries 

from normal brain and brain tumor can help 

to elucidate the tissue-specific gene 

expression at the BTB and distinguish it 

from the tissue-specific gene expression at 

the BBB and normal brain. The elucidation 

of the pattern-specific tissue expression at 

the BBB or the BTB would provide the 

platform for further investigations on overall 

brain capillary biology and brain vasculature 

biology as they pertain to conditions such as 

angiogenesis, cell adhesion, antigen 

presentation, metastasis, and local 

inflammation. 

Priority 3: 

Develop novel viral and non-viral 

strategies for brain tumor gene therapy. 

Viral strategies include the use of 

adenovirus, herpes simplex virus, adenoassociated virus, and other virus vectors. To 

date, investigators conducting trials in 

humans have used virus gene formulations 

administered invasively, through 

intracerebral implantation. Work in 

experimental animals, however, has 

demonstrated that both intra-arterial and 

intravenous delivery can be efficacious and 

safe. Some of the new conditionally 

replicating virus vectors have the added 

advantage of virus amplification within the 

tumor after passage through the BBB, thus 

increasing the treatment volume. 

The developments in Priorities 1 and 2 

should be applied to improve the delivery of 

virus and non-virus vectors to tumors and to 

target the BTB. Current problems include 

the lack of information on the role of the 

immune system in limiting virus replication, 

enhancing tumor rejection, and potentially 

causing brain inflammation. Limitations also 

exist in the methodologies available for 

targeting specific tumor cells in order to 

minimize potential toxicity to normal brain 

and vasculature. Studies have demonstrated 

the synergistic effects of virus vectors with 

other modes of therapy, such as 

radiotherapy, chemotherapy, and 

immunotherapy, but to date these 

approaches have not been applied in 

humans. 

Therapeutic Targeting 21 
RESOURCES NEEDED 

Priority 1 

The development of novel drug targeting 

systems in the brain that enhance brain 

tumor uptake of either small- or largemolecule diagnostics or therapeutic 

molecules requires the following: 

• Inclusion of lipid-soluble drugs that 

penetrate the BBB and of brain tumors 

in industrial and government antitumor 

drug development programs. 

• Novel forms of BTB disruption 

• Drugs that access BBB carriermediated transport systems 

• Drugs that inhibit BBB active efflux 

transporters such as p-glycoprotein 

• New vectors (ligands) that are 

transported across the BBB by 

receptor-mediated transcytosis systems, 

which can act as “molecular Trojan 

horses” for transporting drugs across 

the BBB and BTB 

Priority 2 

Isolated brain capillaries from either animal 

or human brain and human brain tumor 

should be used as the starting point for 

preparing BBB-specific gene arrays and 

cDNA libraries from BBB and BTB. BBB 

gene-specific proteomic programs can also 

be developed in parallel. The focus on these 

genomics or proteomic programs should be 

molecular-based strategies for investigation 

of the following: 

• Tissue-specific gene expression of the 

BBB of normal brain 

• Differences in capillaries perfusing 

normal brain BBB and tumor 

capillaries (BTB) 

• New endogenous BBB or BTB 

transporters for targeted drug delivery 

to brain tumors 

• Novel mechanisms of tumor 

angiogenesis, invasion, cell adhesion, 

metastasis, and antigen presentation 

Priority 3 

Development of vectors and strategies 

for gene/viral delivery to brain tumors, 

taking into account the unique character of 

brain vasculature, extracellular space, and 

cell diversity, will require the following: 

• Novel adenovirus, herpes simplex 

virus, adeno-associated virus, or other 

virus vectors that specifically target 

tumor cells in the brain and do not 

cause brain toxicity 

• Virus or non-virus vectors that target 

brain tumors upon intraarterial or 

intravenous administration. Such 

strategies may utilize the ability of 

some virus vectors to cross the brain 

vasculature and specifically multiply 

within the tumor or may follow the 

development of novel BBB/BTB drug 

targeting systems. 

• Vectors or molecules that specifically 

target the tumor vasculature without 

harm to the normal brain vasculature 

• Strategies that utilize the above vectors 

in combination with radiotherapy, 

chemotherapy, or immunotherapy 

The NCI and the NINDS are urged to adopt 

all three of these priorities, as they are 

interconnected. Gene and viral therapy, use 

of recombinant proteins, monoclonal 

antibodies, or antisense therapy may be 

successful in patients with the adaptation of 

novel BTB drug targeting systems applied to 

brain tumors. However, the discovery of 

novel BBB drug targeting systems will be 

accelerated by the classification of the 

tissue-specific gene expression at the BBB 

through a BBB genomics program. Further, 

the use of any biological agent for brain 

tumor therapy could have immunological 

22 Report of the Brain Tumor Progress Review Group 
problems that are different from those of 

similar therapies administered for non-CNS 

disease. Studies of this immunological 

response need to be supported in order to 

take these agents safely into clinical trial. 

Also needed are future training programs 

focusing on brain vascular biology in order 

to produce a generation of scientists who can 

integrate our knowledge of neuroscience and 

cerebrovascular biology. 

Therapeutic Targeting 23 
Detection and Diagnosis 

Co-Chairs: J. Gregory Cairncross, M.D., and Donna Neuberg, Sc.D. 

Participants: 

Rebecca Betensky 

Jaclyn A. Biegel 

Peter M. Black 

James Boyette 

Pim Brouwers 

Greta Bunin 

Peter Burger 

R. Edward Coleman 

Faith G. Davis 

Lisa DeAngelis 

Pam Del Maestro 

Stuart A. Grossman 

Alison Hannah 

Bruce R. Korf 

Craig Lustig 

Ravi Menon 

Roger Packer 

Roy A. Patchell 

David Ramsay 

Lynn A. Ries 

Lucy B. Rorke 

Malcolm Smith 

Michael Walker 

Mark Yarborough 

STATEMENT OF THE PROBLEM 

Brain tumors are a heterogeneous group of 

central nervous system neoplasms that arise 

within or adjacent to the brain. Some are 

curable by surgical resection, but many 

cannot be eradicated by current treatments, 

and, when they are, disabling neurological 

injury often ensues. Moreover, the location 

of the tumor within the brain has a profound 

effect on the patient’s symptoms, surgical 

therapeutic options, and the likelihood of 

obtaining a definitive diagnosis. The 

location of the tumor in the brain also 

markedly alters the risk of neurological 

toxicities that alter the patient’s quality of 

life. 

At present, brain tumors are detected by 

imaging only after the onset of neurological 

symptoms. No early detection strategies are 

in use, even in individuals known to be at 

risk for specific types of brain tumors by 

virtue of their genetic makeup. Current 

histopathological classification systems, 

which are based on the tumor’s presumed 

cell of origin, have been in place for nearly a 

century and were updated by the World 

Health Organization in 1999. Although 

satisfactory in many respects, they do not 

allow accurate prediction of tumor behavior 

in the individual patient, nor do they guide 

therapeutic decision-making as precisely as 

patients and physicians would hope and 

need. Current imaging techniques provide 

meticulous anatomical delineation and are 

the principal tools for establishing that 

neurological symptoms are the consequence 

of a brain tumor. 

CHALLENGES 

Detection 

Early detection has not been an area of 

interest or focus in neurooncology. Because 

early treatment for many types of brain 

tumors does not improve quality or prolong 

length of life, early detection strategies have 

not been a priority and their use may not be 

ethical. In this respect, brain tumors are 

different from cancers of the breast, prostate, 

and colorectum, for which screening 

strategies are now broadly used in healthy 

populations. Moreover, because the causes 

of brain tumors are not known, it is not yet 

possible to identify special populations that 

are at increased risk due to environmental or 

occupational exposure. 

Imaging, the obvious screening strategy for 

brain tumors, is extraordinarily costly, 

especially given the relative rarity of brain 

tumors in comparison with breast or prostate 

cancer. Genetic testing, a second option, is 

desirable as a screening tool because it is 

24 Report of the Brain Tumor Progress Review Group 
based on a simple blood test, but this 

modality is not yet a reality for sporadically 

occurring brain tumors, which by far 

constitute the majority of brain tumors. 

Hence, the question arises as to whether 

there is a role for early detection strategies in 

neurooncology. 

Detection can also be defined to include 

prompt diagnosis in symptomatic patients, 

early recognition of tumor recurrence in 

previously diagnosed or treated patients, and 

the ability to distinguish between recurrence 

and radionecrosis. In pediatric populations, 

early symptoms of brain tumor can be 

misdiagnosed as migraine, school phobia, 

anorexia, or other common pediatric 

problems. In very young children, the 

symptoms of brain tumor may be dismissed 

as minor developmental delays. An intense 

educational effort is required to ensure that 

children as well as adults receive prompt and 

thorough neurological assessment for 

lingering symptoms. Imaging methods need 

to be able to identify early recurrence and to 

distinguish recurrent disease from other 

pathologies. 

Diagnosis and Prognosis 

The current histopathological approach to 

the diagnosis and classification of brain 

tumors is satisfactory in many respects. In 

virtually all instances, brain tumors can be 

accurately placed into broad diagnostic 

categories, such as gliomas, meningiomas, 

or metastases. Within these categories, 

however, some tumors are not further 

classifiable; concordance in histological 

diagnoses between pathologists is 

sometimes poor; and tissue samples, when 

small, render confident classification 

difficult. Increasingly, tissue samples are 

small because stereotactic biopsy procedures 

are the preferred means to establish a 

diagnosis of brain tumor. In addition, when 

the tumor is located deep within the brain or 

adjacent to eloquent cortex, only stereotactic 

biopsies are feasible. Occasionally a brain 

tumor is treated in the absence of a 

histopathological diagnosis because its 

location precludes safe sampling. 

Another limitation of the current 

histopathological basis of brain tumor 

classification is the inability to accurately 

predict tumor behavior or response to 

therapy . Tumors that look similar may 

behave quite differently, and conversely, 

tumors that look quite different may behave 

identically. Currently, when 

histopathological diagnosis is augmented by 

clinical and radiographic features such as 

patient age and tumor enhancement, 

prognostication for survival in individual 

patients improves but remains inexact. 

Predicting response to treatment by 

histologic, clinical, and radiographic features 

therefore remains elusive. 

Given the rapid advances in gene expression 

profiling, the achievements in sequencing 

the human genome, and the continuing 

revolution in brain imaging, the question 

arises: What is the potential for molecular 

characterization and advanced imaging, 

alone or in combination, to augment or 

replace current histopathological diagnosis 

and tumor classification in neurooncology? 

More important, what is the potential of 

these approaches to predict tumor behavior 

and sensitivity to treatment? These 

possibilities are especially exciting because 

there are already suggestions that specific 

genetic alterations in glial tumors may 

predict survival outcomes after specific 

therapies. 

A further exciting opportunity afforded by 

advances in molecular medicine and 

imaging might be the ability to predict 

response to existing and novel therapies, and 

to do so soon after administering the 

intervention. The ability to streamline the 

assessment of therapeutic maneuvers would 

permit ineffective therapies to be discarded 

Detection and Diagnosis 25 
quickly. This would be especially welcome 

to patients, who perceive that the evaluation 

process is slow, inefficient, and imprecise. 

Having an earlier endpoint by which to 

declare a therapy ineffective would address 

these important concerns. Moreover, early 

identification of effective therapies quickly 

resets the clinical research agenda to include 

quality of life as well as efficacy. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

The successful achievement of the following 

priorities will require advances in brain 

tumor imaging and genetics and will have 

important implications for brain tumor 

treatment. epidemiology, and outcomes. 

Priority 1: 

Develop a molecular- and imaging-based 

classification for brain tumors that is 

capable of predicting tumor behavior and 

guiding treatment decisions more 

accurately and objectively than are 

current histopathological methods. 

Corollary: Investigate whether imaging 

methods can be developed to capture the 

tumor’s molecular signature. This is 

important because the amount of tumor 

tissue available at diagnosis may be limited, 

and tissue is not available for serial sampling 

after therapy. 

Priority 2: 

Refine the ability to detect response to 

novel treatments so that ineffective 

therapies can be discarded quickly while 

active compounds are evaluated fully in 

clinical trials that assess quality as well as 

length of life. Non-anatomical magnetic 

resonance signals, rather than change in 

tumor size, may have the potential to 

accurately detect early response. 

Corollary: Refine the ability to predict 

response to existing treatments so that 

patients receive active agents prescribed 

optimally, and do not receive toxic 

ineffective therapies. Molecular markers or 

imaging signals may have the potential to 

accurately predict response. 

Priority 3: 

Identify serum markers of individual 

brain tumor types in preparation for 

screening programs in at-risk individuals 

or in populations. Screening, using serum 

markers, will be important and ethical 

only when it is clear that early treatment 

unequivocally improves patient outcomes. 

RESOURCES NEEDED 

Tissue banks linked to clinical databases are 

needed for both pediatric and adult brain 

tumors of all types. Tissue banks should 

include both paraffin-embedded and frozen 

tumor, serum, normal DNA from peripheral 

blood or buccal mucosa, and, in certain 

instances, cerebrospinal fluid. For frozen 

tissue, guidelines for quality assurance and 

tissue preparation need to be developed. The 

clinical database should contain information 

about patient characteristics, family history 

of brain tumor or unusual cancer 

susceptibility, imaging features (including 

tumor location), therapy administered, 

response to therapy, and survival. 

A decentralized banking model is 

envisioned. Public and professional 

educational efforts will be required to ensure 

that both common and rare brain tumors are 

submitted to the banks. Large numbers of 

samples will be important to sustain a 

concerted research effort that can address the 

heterogeneity of these diseases and the many 

scientific questions that will arise. When 

available, serial samples should be banked 

on an individual basis. An oversight 

structure will be needed to control access to 

26 Report of the Brain Tumor Progress Review Group 
this precious resource, and patient consent 

issues will need to be carefully considered. 

Detection and Diagnosis 27
Epidemiology, Prevention, and Outcomes 

Co-Chairs: Christina Meyers, Ph.D., and Susan Weiner, Ph.D. 

Participants: 

James Boyette 

Pim Brouwers 

Greta Bunin 

Peter Burger 

Faith G.Davis 

Lisa DeAngelis 

Fred Hochberg 

Peter Inskip 

Carol Krutchko 

Minesh Mehta 

Raymond Mulhern 

Scott Pomeroy 

David Ramsay 

Lynn A.Ries 

Lucy B.Rorke 

Libby Stevenson 

EPIDEMIOLOGY 

Statement of the Problem 

Gaps in the fundamental understanding of 

brain tumors, from basic biological 

interactions to epidemiology, hinder 

systematic approaches to prevention. 

Although research exploiting new molecular 

and genetic technologies is attracting 

scientists and funds, epidemiological 

information about primary brain tumors 

remains scarce. The absence of high-quality 

epidemiological studies is an impediment to 

understanding who and how brain tumors 

arise in both children and adults. 

Challenges and Barriers 

The histopathological variability in brain 

tumors and the relatively small numbers of 

persons affected complicate the design of 

research protocols and historically have 

limited the statistical power of studies. 

Existing tumor registries and surveillance 

systems (including the Surveillance, 

Epidemiology, and End Results [SEER] 

Program and the North American 

Association of Central Cancer Registries 

[NAACCR]) are not linked or structured to 

allow rapid case ascertainment or case 

sample sizes adequate for meaningful 

epidemiological research of all brain tumor 

types. Although promising epidemiological 

clues have been uncovered in recent years, 

few are being pursued through funded 

studies. 

Many previous epidemiological studies on 

primary brain tumors have significant 

methodological flaws. Methodological 

issues themselves warrant investigation to 

advance the field. Questions that need to be 

addressed include how to assess recall bias 

among study subjects who may have 

cognitive impairment; what types of 

exposures for which interview data and the 

potential for recall bias may be strong 

enough to result in spurious associations; 

how the interval between exposure and 

interview may affect recall bias; and whether 

there are feasible sources of control groups 

in the United States other than the current 

approach of random-digit dialing and 

interviews with hospital patients. 

Most registries collect data only on 

malignant tumors, as defined by the 

International Classification of Diseases, 9th 

Edition (ICD-9). That registries are limited 

to malignant tumors artificially constrains 

epidemiological understanding of brain 

tumors. For example, the just-revised 

classification system used by all cancer 

registries now codes juvenile pilocytic 

astrocytomas as benign, and therefore 

registries—including SEER—are likely to 

stop collecting data on these tumors. Brain 

tumor specialists include and treat all 

neoplasia of the central nervous system as 

28 Report of the Brain Tumor Progress Review Group 
cancer, and the rationale for including all 

brain tumors in population-based 

surveillance systems has been well 

documented. 

Better surveillance tools are critical to 

facilitate epidemiological research. Two 

avenues of epidemiological investigation are 

especially compelling. In pediatrics, 

mechanisms are in development for a 

surveillance system that routinely collects 

biological samples of blood and tumor. A 

similar system is needed for adult tumors. 

Research and Scientific Priorities 

Priority 1: 

Enhance and expand the existing 

infrastructure for a surveillance database 

that does the following: 

• Includes all primary brain tumors 

(malignant and nonmalignant, central 

nervous system and extraaxial 

• Is designed with enough flexibility to 

accommodate new histological and 

molecular classifications of tumors 

• Gives individual investigators access to 

rapid case ascertainment for studies 

that require questionnaires, tissue 

samples, pathological review, and 

pooling of results to increase sample 

size. 

SEER and state registries capture 50% or 

more of neuroepithelial tumors, and 

extraaxial tumors can be captured only 

through a central brain tumor registry. 

Approximately 52% of “quality” registries 

cover the U.S. population. If definitions 

were changed by consensus, data from 

diverse sources could be integrated into the 

database of the National Cancer Institute and 

other databases. 

Priority 2: 

Target funding to support basic science 

and population-based human studies to 

evaluate leads on animal 

neurocarcinogens, such as exposure to 

nitrosamines, viral agents, and 

polymorphisms. For known animal 

carcinogens, molecular exposure 

measures are needed to allow direct 

exposure measures for human studies. 

Priority 3: 

Investigate the epidemiology of 

neurotoxicity and other toxic effects of 

treatment, such as what makes some 

patients susceptible and what exerts a 

protective effect. 

Resources Needed 

• Database of household carcinogens. 

A database listing the major household 

sources of known carcinogens (e.g., 

dry-cleaned clothing, oven cleaner, 

specific types of paints, weed killer), 

including neurotoxins and 

neurocarcinogens, would be valuable 

for both brain tumor and cancer 

epidemiology in general. 

• Training. Training in epidemiological 

methods is needed for researchers 

involved in etiological and outcome 

studies, including neurooncology and 

neurosurgery residents. 

PREVENTION 

Statement of the Problem 

Although the literature and the current 

National Institutes of Health (NIH) research 

portfolio hold almost no information 

relevant to the prevention of primary brain 

tumors, factors that may reduce the risk of 

primary brain tumors are gradually being 

identified. Specifically, studies of pediatric 

Epidemiology, Prevention, and Outcomes 29 
cancers suggest that maternal diets high in 

fruit and vegetable intake or maternal use of 

vitamin supplementation, particularly 

folates, during pregnancy may reduce tumor 

development. Other studies suggest a 

protective role for allergic conditions and 

selected infectious diseases in adult tumors. 

If these isolated results can be replicated and 

clarified and the underlying biological 

mechanisms understood, intervention and 

prevention strategies may become feasible. 

Challenges 

At this juncture, not enough is known about 

the basic epidemiology of primary brain 

tumors to guide research initiatives. For this 

reason, the most pressing challenge is to 

acquire data that will drive scientific 

inquiries in prevention. 

Research and Scientific Priorities 

Priority 1: 

Because of the paucity of data and ideas 

about prevention, a request for proposals 

should be issued to stimulate new 

research approaches. 

Priority 2: 

For a subset of brain tumors, some 

information is available to suggest fruitful 

research directions. For example, it may 

be feasible to explore the prevention of 

certain familial cancers, such as 

neurofibromatosis or von Hippel–Lindau 

syndrome. In addition, data from patients 

treated in pediatric cancer cooperative 

groups may yield insights about 

prevention for patients at risk of second 

primary tumors resulting from previous 

cancer treatment. 

OUTCOMES 

Statement of the Problem 

The endpoints of survival and disease-free 

survival, which traditionally have been used 

to assess outcome in patients with cancer, 

fall painfully short as measures of success in 

treating brain tumors. From the perspective 

of patients and families, “outcome” is a 

multidimensional, daily reality, and quality 

of life can be at least as important as 

survival. So, too, assessment of quality of 

life is increasingly used to evaluate the risks 

and benefits of new treatments. 

Researchers who are not directly involved in 

patient care may lose sight of the importance 

of the functional impact of brain tumors and 

their treatment on survivors and the families 

who care for them. Because the current 

treatment armamentarium has little to offer 

many patients with brain tumors, saving a 

life can be a considerable achievement. 

Saving a life without considering future 

constraints on how life can be lived, 

however, may offer an unacceptable 

outcome. Parents want to normalize life for 

an affected child, and adult patients want to 

weigh the functional risks they face with 

each treatment option. 

To allow patients and parents to make more 

informed treatment decisions, clinicians 

need more information on the expected 

functional outcomes of disease and 

treatment. Such assessment data can also 

contribute to the drug approval process, 

when the survival benefits of two treatments 

are not substantially different. Finally, 

greater understanding of the impact of 

treatment can lead to interventions that will 

allow parents and adult patients to 

rehabilitate damaged functioning and 

normalize their lives. 

Posttreatment follow-up of brain tumor 

patients and survivors does not routinely 

include functional assessment, nor is patient 

30 Report of the Brain Tumor Progress Review Group 
functioning routinely evaluated in clinical 

trials. This lack places a serious limitation 

on the ability to weigh the risks and benefits 

of new therapies and to develop strategies to 

improve functional outcomes. In this 

context, “function” includes neurocognitive 

status, symptoms, ability to perform 

activities of daily life, and psychosocial 

status. Another important but neglected 

aspect of assessment and intervention is the 

impact of brain tumor diagnosis and 

treatment on families. Because families are 

the primary caretakers of patients with brain 

tumors, families’ functioning can have a 

profound and direct impact on patients’ 

functioning and quality of life. 

Challenges and Barriers 

A major barrier to the conduct of functional 

assessments is a negative attitude among 

clinicians. Some feel that it should be 

sufficient for a treatment to avert a patient’s 

death. Some clinicians interpret as 

presumptuous patients’ wishes to have 

maximum levels of functioning and minimal 

damage to the central nervous system and 

loss of function. Further, clinicians may feel 

defensive when faced with a patient’s 

serious or unexpected functional deficits. 

Finally, clinicians may be unfamiliar with 

the assessment process and may 

inappropriately feel that assessment is too 

costly and burdensome for patients. 

To incorporate functional assessments into 

the design of clinical trials, two things are 

needed: 

1. Criteria to determine which trials may 

be suitable (functional assessments are 

not an appropriate component of all 

clinical trials) 

2. Identification of the appropriate time 

points during a clinical trial for 

administration of the assessments. 

Research and Scientific Priorities 

The goals in the area of outcomes are to be 

able to predict the impact of the tumor and 

treatment on a patient’s functional status and 

to achieve the best possible outcome. 

Routine functional assessments and 

interventions are necessary to improve 

patients’ functioning and quality of life and 

should become the standard of care for 

patients with primary brain tumors. 

Priority 1: 

Identify the pathogenesis of the injury 

related to the tumor (e.g., rapid versus 

slow growth, site of the tumor), treatment, 

and comorbid processes (for example, 

those involving the neuroendocrine and 

vascular systems and cytokines). To do 

this, the following are necessary: 

• Correlate patient demographic 

characteristics, imaging, and 

cognitive/quality of life assessments. 

• Develop animal models in tandem with 

human studies. 

• Identify markers for patients at risk of 

developing toxic effects (e.g., the 

apolipoprotein E genotype). 

• Develop and assess drugs that might 

offer neuroprotection during primary 

cancer therapy. 

Priority 2: 

Design and evaluate innovative 

interventions to ameliorate undesirable 

symptoms and functional deficits. Studies 

should include the following: 

• Empirical investigations of what 

works—pharmacologic, behavioral, 

cognitive, or a combination of these 

approaches 

• Mechanism-based interventions 

focused on cytokine antagonists, 

neurotransmitter agonists, and 

neuroprotective agents 

Epidemiology, Prevention, and Outcomes 31 
Priority 3: 

Alter primary therapy to reduce toxic 

effects while maintaining efficacy, such as 

conformal radiotherapy, local therapy, 

and reduced doses of radiotherapy. 

To satisfy third-party payers, in anticipation 

of eventual coverage of the cost of such 

interventions, cost-effectiveness should be 

built into the research design prospectively. 

The efficacy of these interventions should be 

correlated with imaging measures, including 

functional magnetic resonance imaging, and 

with physiological correlates, such as levels 

of pro-inflammatory cytokines and 

neuroendocrine markers. 

Resources Needed 

Intra-institutional cooperative research 

initiatives, both within and outside NIH, 

should be fostered to address rehabilitation, 

education, and medical issues. Several 

working groups or consensus panels should 

be convened under NIH auspices to 

accomplish the following: 

• Standardize assessment tools. The 

tools now used to assess patient 

function are not standardized across 

studies, sites, or patient populations. 

Standardized assessment instruments 

will enhance the generalization of 

findings; if a core of standard content 

exists, institutions can tailor aspects to 

specific studies. Tools need to be valid, 

reliable, easy to use, and inexpensive 

to administer. 

A panel of neuropsychologists, 

neurologists and patient advocates 

should select well established, userfriendly instruments from the literature 

to form a “practice guideline protocol” 

for use in evaluating patients in clinical 

trials. Such a protocol of assessment 

instruments can be constructed to 

allow the investigator to select the 

tools that will evaluate hypotheses 

related to, for example, memory, 

attention, language, and spatial deficits. 

• Survey successful interventions. A 

review of cognitive-behavioral and 

psychopharmacological interventions 

used in other rehabilitation-related 

disciplines, such as special education 

and rehabilitative practices related to 

traumatic (acquired) brain injury, 

dementia and aging, and stroke, should 

be undertaken to determine whether 

successful strategies might be used 

successfully with brain tumor patients. 

This review should be comprehensive 

and include projects funded and/or 

conducted through the National 

Institute of Neurological Disorders and 

Stroke, the National Institute of Child 

Health and Human Development, the 

National Institute of Mental Health, the 

National Institute of Dental and 

Craniofacial Research, and other NIH 

and Department of Health and Human 

Services institutions, centers, and 

working groups. Similarly, a review of 

family support interventions developed 

for traumatized families should be 

conducted to cull potentially effective 

interventions for families with a 

member affected by a brain tumor. 

• Develop assessment guidelines. 

Guidelines are needed on what and 

when to assess in different types of 

clinical trials. Currently, questions 

about symptoms such as headaches are 

asked to determine side effects of 

treatment, but patients may also be 

asked questions such as how they feel 

about the symptoms they report. These 

questions are important for patient care 

but vary dramatically from person to 

person and may not be informative in 

clinical trials. It would also be helpful 

for guidelines to be framed with an 

32 Report of the Brain Tumor Progress Review Group 
understanding of the World Health 

Organization’s three-tiered level of 

analysis (impairment, disability, and 

handicap). 

33
Cancer Genetics and Epidemiology 

Co-chairs: Webster K. Cavenee, Ph.D., and Ronald A. DePinho, M.D. 

Participants: 

Francis Ali-Osman 

Rebecca Betensky 

Jaclyn A. Biegel 

Darell D.Bigner 

J. Gregory Cairncross 

Richard A.Fishel 

James F.Gusella 

Daphne A Haas-Kogen 

C. David James 

Bruce R.Korf 

Kenneth A.Krohn 

Greg Riggins 

James Rutka 

Gail Segal 

Jeannine Walston 

Albert Wong 

STATEMENT OF THE PROBLEM 

Concerted efforts over the past few years 

have shown that brain tumors, like other 

major human neoplasms, result from the 

accumulation of genetic lesions during 

tumor progression. Despite the extensive 

catalogue of these somatic tumor-associated 

lesions, significant gaps exist in our 

understanding of how such lesions initiate 

the process, how they influence therapeutic 

response, and the nature of their biological 

function. Clearly, such information will be 

required in order to harness the knowledge 

of genetics for improved diagnostic and 

therapeutic modalities. This is of particular 

importance for this group of tumors, given 

their unique biological and clinical 

characteristics and heterogeneity. 

CHALLENGES AND QUESTIONS 

• Little is known about brain tumor 

predisposition genes in humans. This 

situation reflects the scarcity of 

specimens, poor record-taking of 

family medical histories, insufficient 

clinical and pathological information 

on the samples, the lethality and late 

onset of many of these diseases, the 

inaccessibility of early lesions, and 

pedigrees that often do not lend 

themselves to mendelian analysis. In 

rare instances, autosomal dominant 

patterns indicative of “hard” primary 

mutations have been reported (e.g., 

Turcot syndrome, neurofibromatosis 1 

and 2, and Li-Fraumeni syndrome). 

Family patterns are more commonly 

consistent with the possibility of 

multigenic inheritance (“soft” but 

interacting mutations), modifiers that 

alter the penetrance or expressivity of 

the genes, or epigenetic gene 

inactivation. 

• A special feature of many malignant 

brain tumors is their innate resistance 

to existing chemo- and 

radiotherapeutic approaches. Little is 

known about the genetic mechanisms 

responsible for this resistance. For 

example, the impact of somatic or 

germline allelic variation on these 

mechanisms remains to be determined. 

• Limited information exists on how 

specific lesions behave in cells of 

different lineages thought to represent 

precursors of distinct brain tumor 

types. Such information could be of 

importance in the design of therapeutic 

protocols targeting such lesions. 

• Little is known of the interactions 

between predisposing/somatic 

mutations and external or internal 

environmental perturbations, such as 

hormonal influences, in utero 

exposures, and workplace carcinogens. 

This issue might be particularly 

relevant in explaining tumor 

emergence in different age groups 

34 Report of the Brain Tumor Progress Review Group 
(pediatric versus adult) and their 

distinct clinical behaviors. 

• The genetic basis of the unique 

biological features of brain tumors is 

largely not understood. This applies to 

integral and important features such as 

invasion, motility, angiogenesis, and 

necrosis, as well as tumor progression 

and maintenance. 

• Existing genetic models and associated 

genomic infrastructure (particularly in 

mice) are inadequate to properly 

address the genetic and phenotypic 

aspects of the human diseases. In the 

absence of validated, refined models, 

rapid testing of candidate cancer genes 

and their therapeutic approaches is 

severely hampered. 

• There is an inadequate compendium of 

gene expression profiles for precursor 

cells and their lineages and tumor 

derivatives. Little information exists on 

the nature of the physical and 

functional interactions of the gene 

products that are known to play a role 

in the development of brain neoplasia 

with other cellular components. 

Moreover, genome-wide genotypes 

have not been collected and so have 

not been tested for their correlation 

with tumor type or behavior. 

• There exists a strong need for the 

development of genetic screens that 

will permit tumorigenesis. These 

screens need to be conducted on both 

the organism and cell levels. The latter 

will be depend on the development of 

in vitro systems that accurately reflect 

the in vivo process under investigation. 

• There is no comprehensive tumor 

registry, tumor bank, and familial 

tissue bank. It is especially important 

that these be comprehensive and 

organized on a national level, given the 

rarity and heterogeneity of the most 

informative tumors and familial 

situations. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Isolate genes causing predisposition to 

human brain tumors. 

It is important to search for predisposition 

genes in families with brain tumors as the 

primary identifier of genes relevant to brain 

tumors. Families whose members are prone 

to a variety of other tumors may represent 

additional opportunities to isolate genes that 

are also relevant to brain tumor 

pathogenesis. Elucidation of the interaction 

of such genes with environmental agents 

may also play a significant role in 

understanding the etiology of brain tumors. 

Priority 2: 

Identify the genes and genetic variations 

that underlie tumor resistance to 

chemotherapy and radiation therapy, as 

well as the allelic variations that influence 

responses to therapy in individual 

patients. 

Priority 3: 

Understand genotypic influences on 

phenotypic behavior, tumor type, age at 

onset, anatomical position, cell of origin, 

and cellular biology. 

Priority 4: 

Establish and refine genetically based 

model systems that can faithfully 

recapitulate the complexity, 

heterogeneity, and diversity of human 

brain tumors. 

Cancer Genetics and Epidemiology 35 
RESOURCES NEEDED 

• There is a strong need for organized 

and coordinated brain tumor registries, 

including family histories and 

extensive clinical and pathological 

information. These registries should be 

coupled with tumor samples that are 

equally well characterized and with 

somatic noncancerous tissues from 

affected individuals and their family 

members. It would be particularly 

useful if such centralized resources 

maintained strong technical support to 

conduct routine genome-wide studies, 

including expression profiling, in situ 

hybridization of tissue arrays, and 

high-density genotyping and mutation 

analysis. Centralization of these 

technical efforts would provide for 

efficient and thorough utilization of 

these precious samples and enable 

investigators to obtain such 

information without the need to build 

or develop advanced capabilities 

themselves. 

• It would be widely useful to establish a 

compendium of gene expression 

patterns and genome-wide genotypes 

of tumors of many different histologies 

to be used for correlative studies with 

regard to cell type, developmental 

stage, and their response to therapeutic 

agents. The Brain Tumor Genome 

Anatomy Project BT-GAP and the 

Cancer Genome Anatomy Project 

(CGAP) are making significant 

progress with regard to human tumors, 

but the genome infrastructure to 

analyze mice lags far behind. This is a 

serious problem in that it hampers the 

rapid isolation of genes based on 

interspecies sequence homologies. 

• There is a strong need to support the 

design and development of novel and 

targeted genetic screens conducted on 

both the organism and cell culture 

levels. Particularly relevant is the need 

to fortify efforts for the development 

and refinement of mouse models of 

human brain tumors harboring 

commonly occurring genetic lesions. 

Such cancer-prone models will find 

great utility in the identification of 

pathways and their interactions, as well 

as for loci that modify the effects of 

these pathways. Significant emphasis 

should be placed on the development 

and design of mouse models that 

enable assessment of the role of genes 

in both tumor initiation and tumor 

maintenance. 

• The interdisciplinary nature of 

neurooncology makes it essential to 

augment the opportunities for 

physicians to receive training in 

molecular oncology and developmental 

neurobiology. It is equally essential for 

basic scientist trainees to receive 

training that is medically relevant to 

molecular neurobiology. Similarly, 

there exists a need for programmatic 

funding mechanisms that can form a 

bridge between the activities of 

established investigators from different 

disciplines focused on common themes 

in neurooncology. The design of the 

peer review of such grants should 

consider the special needs and 

circumstances of such interdisciplinary 

efforts. Finally, the relative paucity of 

understanding of this dread disease 

underscores the desirability to develop 

rapid funding mechanisms 

emphasizing novel and, perhaps, 

preliminary ideas (cf. Department of 

Defense “concept grants”). 

36 Report of the Brain Tumor Progress Review Group 
Imaging 

Co-chairs: Ronald G. Blasberg, M.D., and John C. Mazziotta, M.D., Ph.D. 

Participants: 

Ramon Gilberto Gonzalez 

Fred Hochberg 

Kenneth A. Krohn 

Kathleen R. Lamborn 

Sarah J. Nelson 

Edward A. Neuwelt 

William M. Pardridge 

Bruce R. Rosen 

Gail Segal 

Arthur W. Toga 

STATEMENT OF THE PROBLEM 

The past 60 years have seen a progression in 

the field of imaging from the early use of 

cerebral angiography and 

pneumoencephalography to the development 

of early radionuclide techniques and the 

advent of X-ray computed tomography (CT) 

in the 1970s. The current era has seen the 

implementation of magnetic resonance 

imaging (MRI) in all its permutations 

(structural, functional [fMRI], perfusion, 

diffusion, and spectroscopy), single-photon 

emission computed tomography (SPECT), 

positron emission tomography (PET), and 

intraoperative ultrasound. These techniques, 

now part of the clinical mainstream, are used 

individually or in combination to better 

understand the basic mechanisms, 

pathophysiology, and clinical features of 

brain tumors and their responses to therapy. 

They are also used to make therapy safer and 

more accurate, ultimately improving the 

quality and duration of life for patients. 

Functional imaging—the visualization of 

physiologic, cellular, or molecular processes 

in living tissue—now provides insights into 

tumor blood flow, glucose or oxygen 

metabolism, and many other hemodynamic, 

physiologic, and biochemical processes. 

Such approaches may provide a means to 

identify molecular structures or receptors 

that cover the surface of a tumor and to help 

predict its natural history and response to 

certain treatments. Attempts are already 

being developed to use such strategies to 

examine gene expression, a strategy that will 

improve detection, staging, treatment 

selection, treatment monitoring, and 

prognosis. Imaging techniques are also now 

being linked to surgical and radiation 

therapies. Pre- and intraoperative imaging 

methods using CT, MRI, PET, and SPECT, 

as well as intraoperative methods such as 

radioisotope probes, optical imaging, and 

intraoperative MRI, are all finding a place in 

planning surgical or radiation therapy for 

patients and in sampling or targeting tissue 

for biopsy. These technologies also have a 

role in avoiding critical brain areas when 

destructive lesions or surgical resections are 

planned. They may also be important in 

evaluating the plasticity of normal brain 

tissue after such procedures, either during 

development in pediatric brain tumors or in 

adults. 

The development of cellular- and molecularbased imaging will provide many new 

opportunities to assess brain tumors at a 

molecular level in animal and clinical 

models, as well as the ability to monitor 

gene therapy. As imaging techniques 

continue to evolve, it will be possible to 

visualize and quantitate changes as cells 

transform from normal to precancerous to 

cancerous. It may one day be possible to 

evaluate at-risk patients earlier in cancer 

pathogenesis, perhaps before a tumor 

becomes malignant. It is anticipated that, 

with the information obtained from the use 

Imaging 37 
of such imaging techniques, it will be 

possible to visualize the actual molecular 

signatures of cancer in vivo. The ability to 

detect fundamental changes associated with 

a tumor cell will thus vastly improve our 

ability to detect and stage tumors, select 

appropriate treatments, monitor the 

effectiveness of a treatment, and determine 

prognosis. 

For example, patients may be selected for a 

particular drug therapy on the basis of 

imaging before drug administration. A 

drug’s effect on specific protein interactions, 

signal transduction, or metabolic pathways 

could be measured, thereby providing new 

endpoints for monitoring drug response. In 

all probability, nomograms of response 

could be created for populations receiving 

therapies. Clinicians would benefit from 

quantitative methods for the identification of 

“partial response” and “complete response.” 

These would serve as endpoints to replace 

survival in clinical trials. 

In imaging, as elsewhere in cancer research, 

animal models of cancer are making it 

possible to perform certain kinds of studies 

that are difficult, if not impossible, to 

perform in humans because of practical or 

ethical considerations. A distinct advantage 

of noninvasive imaging in animal models of 

cancer is the ability to perform repetitive, 

noninvasive observations of the biologic 

processes underlying cancer growth and 

development without sacrificing the animal. 

The development of small-animal imaging 

devices, which can produce serial images of 

experimental brain tumors in small animals 

and incorporate all of the functional 

strategies just described, should provide a 

powerful new tool for experimental studies 

of brain tumor behavior and response to 

treatments. Further development of targeted 

contrast agents, ligands, and imaging probes 

also need to be supported because they will 

provide better in vivo elucidation of the key 

metabolic pathways and specific cell cycle 

functions that become altered in cancer. 

It is also clear that better use can be made of 

existing data derived from imaging 

techniques. Combining in vivo phenotypic 

information about tumor characteristics with 

ex vivo analysis at genetic, cellular, and 

chemical levels can provide better 

correlations among these variables and the 

patterns seen in images obtained in vivo. 

Four-dimensional (spatial and temporal) 

data analysis of these characteristics should 

provide new insights into the natural history 

of tumor growth, patterns of spread, and 

responses to therapy. When optimized into 

probabilistic data structures that account for 

variance, not only in normal brain structure 

but also in tumor behavior, these approaches 

should provide new and useful tools for 

optimizing clinical trials. Image analysis 

techniques that integrate information across 

modalities, spatial and temporal scales, 

subjects, trials, and species will require the 

development of new algorithms; an 

emphasis on neuroinformatics for the 

incorporation of images into clinical trial 

databases; and the incorporation of genetic, 

demographic, and clinical data sets. 

CHALLENGES AND QUESTIONS 

The goals of the National Cancer Institute’s 

plan for Fiscal Year 2001 with regard to 

imaging are quite appropriate to the 

challenges associated with imaging brain 

tumors. These goals include the following: 

• Develop and validate imaging 

technologies, probes, and radiocontrast 

agents that have the sensitivity to 

detect precancerous abnormalities and 

very small cancers. 

• Develop imaging techniques that 

identify the biological properties of 

precancerous or cancerous cells that 

will predict clinical course and 

response to interventions. 

38 Report of the Brain Tumor Progress Review Group 
• Develop minimally invasive imaging 

technologies that can be used in 

interventions and assessment of 

treatment outcomes. 

• Foster interactions and collaboration 

among imaging scientists and basic 

biologists, chemists, and physicists to 

help advance imaging research. 

• Create infrastructure to advance 

research in developing, assessing, and 

validating new imaging tools, 

techniques, and assessment 

methodologies. 

Each of the goals listed above is associated 

with a set of challenges and questions. The 

major challenge for the imaging community 

is to accurately measure tumor burden and 

function (phenotype). This goal will be 

pursued by using different imaging 

technologies, probes, and paradigms (see 

Exhibit 1) in order to better characterize 

brain tumors before, during, and after 

treatment. A further challenge will be 

validation of the new imaging paradigms 

through animal experiments, in vivo versus 

ex vivo (molecular) analysis, and clinical 

correlations. 

One goal of surrogate marker imaging is 

differentiating the cellular and molecular 

characteristics of tumor from those of 

normal brain tissue. Another goal is to 

image the biology (molecular biology) of 

brain tumors with new techniques and 

probes. A final goal is to arrive at non-lethal 

endpoints for the assessment of treatment 

and the natural course of tumor growth. This 

can be done with the development of fourdimensional nomograms specific for tumor 

and age of patient and with spatial-temporal 

measurements, using a multimodality, 

multispectral approach. 

Image Outcome and Monitoring 

Interventions 

Imaging has a role in monitoring both 

treatment progress and outcomes in addition 

to drug toxicity. Available radiographic 

endpoints are inadequate as treatment 

markers and endpoints. Efforts must be 

made to achieve realistic criteria (“cut 

points”) for partial and complete response to 

therapy and to define criteria for assessing 

toxicity to white matter, cortex, and 

ventricular structures. In the case of 

treatment, there are several aspects under 

consideration, each with its own challenges. 

Drug effectiveness should be assessed 

within the context of tissue concentration 

(labeled drugs, etc.), drug delivery of small 

versus large molecules (i.e., blood-brain 

barrier, blood-tumor barrier), and biological 

effect (function) of the tumor. 

Image-guided strategies include the 

following: 

• Preoperative and intraoperative 

planning (e.g., image-guided 

stereotactic biopsy and resection using 

PET, MR, fMRI, magnetic resonance 

spectroscopy [MRS], and optical 

intrinsic signal [OIS] imaging) 

• Radiation therapy (e.g., image-guided 

stereotactic radiosurgery using PET, 

MR, fMRI, MRS, and OIS) 

• Development of multimodal image 

registration (e.g., MR, fMRI, MRS, 

OIS, and PET) 

• Development and availability of 

improved instrumentation (e.g., highfield human MR systems) and hybrid 

imaging devices (e.g., combined CTPET or MRI-PET tomographs) 

Assessment of Treatment Toxicity 

Radiation and chemotherapy can have toxic 

effects not only for the tumor they are 

intended to treat but for brain function as 

Imaging 39 
well. Toxicity to brain white matter has 

received little attention in the past, and little 

is known regarding the mechanism (e.g., 

demyelination, axonopathy, edema) of this 

toxicity and its temporal course. Toxicity 

can also be gauged by imaging the 

vasculature of normal brain and tumor. 

Similarly, toxicity indices can be created for 

gray matter function and plasticity in treated 

children. 

Transgene and Molecular-Based 

Therapies 

Imaging at the molecular level (assuming a 

homogeneous region of interest) is on the 

horizon. The task will be to generate 

reporter gene constructs that can be imaged 

as markers for transgene delivery (e.g., viral 

vectors) and for markers of change in 

specific protein interactions, signal 

transduction, or metabolic pathways. These 

protein interactions and the specific steps in 

signaling pathways can be targeted by 

specific anti-tumor drugs, and drug efficacy 

assessments can be made by noninvasive 

imaging of the specific pathway. In the 

future, patients may be selected for therapy 

on the basis of imaging before drug 

administration. Response could be 

monitored by measuring changes in specific 

protein interactions, signal transduction, or 

metabolic pathways. In this way, new 

endpoints for monitoring drug response 

could be developed. 

Development of Databases, Informatics, 

Standards, and Software Tools 

The NCI has created brain tumor study 

groups offering Phase I and II studies that 

provide the basis for intergroup Phase III 

trials. Examples include the nationwide 

approaches to brain lymphoma and 

oligodendroglioma. It is important to 

translate the above-described imaging 

advances to serve clinical trials. Systems 

must be provided for sharing, accessing, 

archiving, and integrating information across 

all data types. Databases provided for these 

clinical trials must contain real-time imaging 

displays as well as quantitative data (e.g., 

volume, spectral ratios, diffusion ratios, and 

normalized cerebral blood flow [CBF] and 

volume [CBV] information). The field of 

informatics is growing rapidly in the 

biological sciences and can make a major 

impact in the area of brain tumor research. 

Unlike other organs in the body, the brain 

has a distinct and important architecture. 

Both the type and location of brain tumors 

are therefore important in understanding 

their causes, growth patterns, and response 

to therapy. 

A logical framework for integrating 

information about these lesions would be to 

use the anatomical structure of the brain 

itself as the framework for an 

atlas that would store information about all 

patients, whether studied in scientific 

protocols or undergoing conventional 

clinical treatments. Imaging can provide this 

architecture for databases and atlases. It will 

be important to develop the tools and 

informatics methods to integrate imaging 

studies across modalities, spatial-temporal 

scales, subjects, trials, and species. Such 

databases and atlases should be fourdimensional (three in space and one in time, 

where the latter variable can be the age of 

the subject as well as the time course of 

tumor growth and treatment). Because brain 

anatomy is highly variable among 

individuals in a population, it is also 

advisable that such atlases be probabilistic in 

nature, thereby providing distribution 

estimates for the locations of regions and 

tumors. These four-dimensional, 

probabilistic, image-based databases can be 

linked to other data sets, including clinical, 

molecular, histological, and therapeutic 

variables. 

To accomplish such an endeavor, it will be 

important to develop tools to normalize 

40 Report of the Brain Tumor Progress Review Group 
image acquisition across sites and to develop 

a standardized core image analysis and 

feature-extraction pipeline for the 

quantitative processing of imaging studies 

from all modalities. For example, a 

nationwide trial for the therapy of brain 

lymphoma in 600 patients can provide 

seminal data on the rate of response, 

relationship between drug dose and 

volumetric diminution of tumor, changes in 

spectra of magnetic resonance, and diffusion 

parameters. The clinical trials format is the 

ideal mechanism by which reliance on 

individual data sets can be replaced while 

providing integration across laboratories and 

experimental trials. This important, final 

recommendation is critical and, based on 

experiences in other fields, will require 

appropriate funding to provide the force for 

data integration. It will be necessary to 

create data standards (e.g., voxel size, 

diffusion weighted imaging (DWI) software 

sharing) and communication pathways and 

brain atlases at nationwide meetings. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

The following research priorities were 

identified for brain tumor imaging and are 

further detailed in Table 1: 

Priority 1: 

Develop and validate new imaging 

markers and techniques to facilitate the 

spatial-temporal assessment of brain 

tumors. These will be applied to animal 

models, human phase I trials, and phase 

II–III clinical trials. (See Exhibit I for 

details of new probes, markers, and imaging 

techniques based on current imaging 

technology.) 

Priority 2: 

Develop imaging techniques for 

predicting outcome and for planning and 

monitoring interventions in patients with 

brain tumors. 

Priority 3: 

Develop databases, standards, and 

software tools that integrate 

demographic, clinical, and imaging 

information in a form that can be used to 

identify characteristics that are critical 

for managing brain tumors and tailoring 

therapy to individual patients. 

RESOURCES NEEDED 

Resources needed to address these 

challenges include the following: 

• Continuation and expansion of the 

imaging research programs described 

in Exhibit II 

• Development of a “shared” and 

“accepted” informatics and database 

infrastructure 

• Meetings to facilitate relations among 

industry, academics, regulatory, and 

funding agents 

• Research and training funds to support 

the scientific priorities 

Imaging 41 
Table 1: Scientific priorities for imaging in the study of brain 

tumors 

I. Develop and validate imaging markers for the spatial-temporal assessment of brain

tumors for use in human research, clinical trials, animal models, and patient care.

A. Assess tumor burden as non-lethal endpoints for treatment assessment and natural

course.

B. Develop tumor- and age-specific spatial-temporal nomograms (four dimensional).

C. Multimodality, multispectral approach

D. Validation via:

1. Clinical correlation

2. Molecular correlations

3. In vivo vs. ex vivo analysis

E. Validated for:

1. Monitoring treatment

2. Targeting biopsies

F. Differentiating tumor from normal brain

1. Preoperative planning

2. Intraoperative planning

G. Angiogenesis and tumor phenotype imaging

II. Image outcome and monitor therapy in patients with brain tumors.

A. Treatment

1. Drugs

a. Tissue concentration—labeled drugs, etc.

b. Drug delivery—blood-brain barrier, blood-tumor barrier

c. Small vs. large molecule

2. Image-guided strategies

a. Preoperative and intraoperative planning

b. Hybrid devices

c. Small-animal imaging

3. Molecular

a. Reporter gene imaging

i. Transcription of endogenous genes

ii. Post-transcriptional modulation of mRNA

iii. Protein interactions

b. Genotypes—antisense imaging strategies

4. Radiation

a. Tumor

b. Brain

c. Vasculature

B. Toxicity

1. White matter

a. Mechanism (demyelination, axonopathy, edema, etc.) as function of age

and treatment plan

b. Temporal course

2. Vascular

42 Report of the Brain Tumor Progress Review Group 
a. Mechanisms 

b. Temporal course 

3. Gray matter 

a. Mechanisms 

b. Temporal course 

c. Plasticity 

III. Develop databases, informatics, standards, and software tools to: 

A. Integrate across modalities, spatial-temporal scales, subjects, trials, and species 

B. Develop four-dimensional probabilistic image databases linked to databases of 

clinical, molecular, histological, and other variables 

C. Develop tools to normalize across image acquisition sites and to standardize a 

core image analysis and feature extraction pipeline (e.g., post-processing, 

distribution, etc.) 

D. Alter the sociology of data sharing 

Imaging 43 
EXHIBIT I:

New Probes/Markers and Imaging Techniques Based on Current

Imaging Technology

I. MRI B. Toxicity: 

A. Surrogate markers: 

1. Methods need to be 

developed for choosing 

among many options; for 

example, using MRI alone, 

one can assess tumor volume, 

hemodynamics (CBF, CBV, 

BBB permeability), tissue 

water diffusion, and blood 

O2, as well as proton and 31PMRS. At present, it is 

impossible to perform all 

these imaging 

motifs/measurements well, 

and there is little 

standardization of techniques 

across sites. 

2. An overall concern is how to 

pick and choose among the 

different MRI motifs (let 

alone nuclear, CT, and other 

imaging techniques), select 

targets for validation, and 

compare studies by using the 

different imaging methods in 

the study of different patient 

groups with different 

endpoints. 

3. Priorities and challenges 

might include both 

technology development 

(needed to facilitate improved 

quantification, especially for 

MRS and fMRI) and basic 

clinical validation studies 

(although the challenge above 

holds true here). 

4. Ways need to be found to to 

standardize acquisition across 

multicenter trials with 

industrial collaboration. 

1. There is an apparent clinical 

need for functional cognitive 

studies. Because other 

sessions, especially the 

Radiation Therapy session, 

identified the same need, this 

call should be heeded. 

2. fMRI can be combined with 

anatomical, biological, and 

functional assessment of 

white matter changes. 

fMRI/DWI tomography 

would be one priority, and 

the other imaging modalities 

described below would also 

be involved. 

3. Assessment of vascular 

toxicity/BBBs in this 

category will overlap with 

surrogate markers, especially 

for anti-angiogenic 

treatments. Hemodynamics is 

a near-term goal for MRI. 

C. Imaging Therapeutic Effect: 

1. It is difficult to precisely 

define the need for 

quantitative in vivo 

pharmacodynamics within 

the tumor. This issue seems 

largely relegated to nuclear 

imaging, but MRS is likely to 

play some role as well. The 

area of pharmacodynamics 

represents an opportunity for 

industrial collaboration (e.g., 

by major pharmaceutical 

corporations) in a national 

effort to radiolabel all 

prospective therapeutic drugs. 

2. Gene expression presents a 

“grand challenge.” MRI/MRS 

44 Report of the Brain Tumor Progress Review Group 
is likely to play an important 

role in this new field of 

“molecular imaging”; it has 

the right elements and will be 

developed further in the 

decade ahead. 

II. MRS has been a tool for examining the 

alterations in cellular metabolites associated 

with carcinogenesis and treatment response 

in animal and cell systems for more than 20 

years. Recent developments in technology 

have allowed MRS to be increasingly 

routinely applied to patients with brain 

tumors in research and clinical studies. 

There are three major areas for 

development: 

A. Single voxel water suppressed 

proton MRS is the most widely 

available MRS technique for clinical 

applications. It has been shown to 

assist in characterizing tumor type and 

grade, distinguishing tumor from other 

mass lesions, and determining whether 

changes in lesion morphology 

correspond to tumor recurrence or 

treatment-induced necrosis. Challenges 

to this technology include the 

following: 

1. Choosing the most 

appropriate region of the 

lesion to study 

2. Developing databases of in 

vivo spectral characteristics 

and using pattern recognition 

techniques to identify 

fingerprints that are 

predictive of histology 

3. Validating the in vivo 

findings by correlating them 

with results obtained by ex 

vivo analysis of molecular 

markers, histology, and 

nuclear magnetic resonance 

(NMR) spectroscopy of 

excised tissue 

4. Educating radiologists and 

oncologists concerning the 

most appropriate applications 

of the technology and the 

interpretation of the 

biological significance of 

clinical MRS data 

B. Single-voxel proton MRS techniques 

can only interrogate regions that are 

thought to be suspicious from 

morphological or other physiological 

criteria. Proton MRSI can be used to 

map out spatial heterogeneity in both 

the lesion and surrounding tissue for 

studies in animal tumor models and 

patients. Applications include directing 

tissue biopsies, planning surgical 

resection or other focal therapies, 

defining the extent of disease, and 

evaluating response to therapy. 

Challenges to this technology are as 

follows: 

1. The need for improved data 

acquisition techniques for 

optimized shimming, more 

robust water and lipid 

suppression, more accurately 

tailoring the excitation to the 

region of interest, and 

improving signal-to-noise 

ratio by using either higher 

field magnets or more 

sensitive, custom-designed 

radiofrequency coils 

2. Developing post-processing 

methods for displaying 

imaging and spectral data, 

registering serial data from 

follow-up examinations, and 

deriving quantitative indices 

describing the metabolic 

changes within the lesion and 

surrounding normal tissue 

that can be used for treatment 

Imaging 45 
plannig and assessing 

response to therapy 

3. Validation of the technology 

as a tool for routine clinical 

evaluation of brain tumor 

patients in both single and 

multi-institutional settings 

C. Multi-nuclear MRS: At present, the 

applications of 31P, 13C, and 19F MRS 

are limited by low sensitivity and 

mainly involve cell and animal model 

systems. In cases where specific drug 

therapies have a signature that can be 

detected using one of these 

methodologies, there is promise for 

noninvasive monitoring of drug 

delivery and function. More generally, 

it is possible to measure pH, cellular 

bioenergetics, and phospholipid 

metabolism. Challenges for this 

technology include the following: 

1. Obtaining 13C-labeled drugs 

at a price that is economic for 

routine basic and clinical 

research studies 

2. Availability of high field 

human MRI scanners in order 

to obtain in vivo 13C, 19F, and 

31P data at adequate signal-tonoise and spatial resolution 

III. Recent developments in CT merit its 

consideration as a relatively inexpensive and 

widely available method for assessing 

physiological responses to brain tumor 

therapy. The development of the helical 

scanning technique and, most recently, 

multi-detector technology permits the 

measurement of CBF at very high spatial 

resolution with high precision and accuracy. 

This technology is moving rapidly and is 

likely to become the predominant CT 

technique in the course of the next few 

years. This capability and widespread 

availability presents an opportunity for 

inexpensive and widely available functional 

imaging of brain tumors. It is expected that 

high-resolution, high-precision CBF and 

vascular permeability imaging will be most 

amenable for assessment of anti-angiogenic 

therapies. It is possible, perhaps likely, that 

it will be useful for evaluating a wide variety 

of novel therapies. For these reasons, it is 

prudent to encourage explorations in the use 

of this technology in the evaluation of brain 

tumors. 

IV. Nuclear (PET, SPECT, gamma 

camera; special topics that require further 

development) 

A. Cell proliferation (assessment within 5 

years) 

1. Established probe: 11C-TdR 

2. Developing probes: 18F3’FLT, 124I-IUdR, 76BrFbrAU 

B. Angiogenesis (validation of assays for 

monitoring anti-angiogenesis therapy, 

assessment within 5 years) 

1. Blood flow (15O-water, 99mTcsestamibi, 201Tl-thallium, 

133Xe-saline, etc.) 

2. Blood volume (15O- or 11Ccarbon monoxide–labeled 

erythrocytes [RBCs], or 

99mTc-RBCs) 

3. Capillary permeability (82Rbrubidium, 68Ga-DTPA, 68Gatransferrin, 18F-, 123I-, 131I-, 124I- or 99mTc- labeled 

albumin) 

4. Oxygen metabolism (15Ooxygen) 

C. Hypoxia (assessment within 5–7 years) 

1. Established probe: 18Ffluoromisonidazole 

2. Developing probes: 61Cu- or 

64Cu-ATSM, 18F-EF1, 18FEF5, others 

46 Report of the Brain Tumor Progress Review Group 
D. Transporter up-regulation (assessment 

within 5–7 years) 

1. Amino acid transporters (11Cmethionine, 18F-FET, 18FFACBC, etc.) 

2. Nucleoside transporters (11CFMAU, etc.) 

3. Choline transporter (18Ffluorocholine) 

4. Glucose transporter (11C3OMG, 18F-FDG) 

5. Other substrates 

E. Cell surface receptors/antigens 

(endothelial cells and tumor cells; 

assessments over next decade) 

1. Transferrin receptor (67Gatransferrin, 111In-DTPA 

transferrin chelate, etc.) 

2. EGF receptor (radiolabeled 

antibody or peptide) 

3. Benzodiazepine receptor 

(iodinated-PK11195) 

4. Other cell surface 

receptors/antigens (e.g., Flt1 

and Flk1/KDR receptors for 

VEGF) 

F. Cell matrix antigens (assessments 

over next decade) 

1. Integrins (RGD- and other 

radiolabeled peptides 

G. Molecular imaging strategies/issues 

(assessments over next decade) 

1. Reporter gene imaging 

(indirect assay; principle 

established) 

2. Enzymatic amplification vs. 

receptor binding and 

internalization 

3. Oligonucleotide/aptamer 

(direct binding/assay of 

mRNA/proteins; to be 

established) 

4. Probe/contrast agent delivery 

issues (small molecules vs. 

macromolecules) 

H. Molecular imaging specifics 

(assessments over next decade) 

1. Endogenous gene expression 

(transcriptional 

activation/depression) 

2. Post-transcriptional 

modulation/stabilization of 

mRNA 

3. Protein-protein interactions 

of specific steps in selected 

signal transduction pathways 

I. Gene therapy (assessments over next 

decade) 

1. Vector delivery and transgene 

expression (reporter 

transgene imaging 

established) 

2. Trafficking and targeting of 

genetically modified T cells 

V. Optical intrinsic signal (OIS) imaging: 

A. The development of more rapid, 

sensitive, and efficient optical 

instrumentation with multispectral 

capabilities, in order to observe the 

etiology of various functionally active 

cell types in normal and pathogenic 

tissues 

B. Imaging systems compatible with 

interoperative MR environments 

C. The ability to examine molecular 

concomitant to intraoperative optical 

measurements using probes and other 

markers 

D. Compatibility between other 

intraoperative instrumentation and 

optical acquisition and display, such as 

microscopes, stereotactic localizers, 

etc. 

E. Co-localization of multimodality 

displays, including optical, pre- and 

Imaging 47 
intraoperative imaging, tomographic, 

and projection data 

F. The ability to combine intrinsic and 

tracer-based optical images 

G. New optical contrast agents to identify 

specific aspects of brain and brain 

tumor biochemistry. To a large extent 

these agents can be constructed as 

modifications of the nuclear probes. 

48 Report of the Brain Tumor Progress Review Group 
EXHIBIT II:

NCI Imaging Research Priorities

Cellular and Molecular Imaging in 

Cancer: The Goals 

Over the past several years, the National 

Cancer Institute (NCI) has been keenly 

aware of the potential power of imaging 

techniques and molecular imaging in 

particular. The Biomedical Imaging Program 

(BIP) (http://cancer.gov/bip/default.htm) 

of the Division of Cancer Treatment and 

Diagnosis is responsible for the extramural 

grant portfolio and programs related to 

oncologic imaging. Imaging has been 

identified as an area of “Extraordinary 

Opportunity” in the past several “NCI 

Bypass Budgets” 

(http://2001.cancer.gov/imaging.htm). The 

NCI Bypass Budget 

(http://2001.cancer.gov/2001.htm) is a 

public document produced annually by NCI 

to identify for the Administration and 

Congress those scientific priorities on which 

the budget appropriation will be spent. The 

imaging-related goals of the NCI include: 

i. Develop and validate imaging 

technologies and agents (e.g., probes, 

radiocontrast agents) that have the 

sensitivity to detect precancerous 

abnormalities or very small cancers. 

ii. Develop imaging techniques that 

identify the biological properties of 

precancerous or cancerous cells that will 

predict clinical course and response to 

interventions. 

iii. Develop minimally invasive imaging 

technologies that can be used in 

interventions and in assessing treatment 

outcomes. 

iv. Foster interaction and collaboration 

among imaging scientists and basic 

biologists, chemists, and physicists to help 

advance imaging research. 

v. Create infrastructures to advance 

research in developing, assessing, and 

validating new imaging tools, techniques, 

and assessment methodologies. 

The NCI has already made significant 

progress in the past several years toward 

reaching these goals with the introduction of 

various programs and initiatives: 

• NCI has awarded three grants to 

support In-Vivo Cellular and Molecular 

Imaging Centers (ICMIC) 

(http://grants.nih.gov/grants/guide/rfafiles/RFA-CA-99-004.html). The ICMIC 

grants will facilitate interaction among 

scientists from a variety of fields to conduct 

multidisciplinary research on cellular and 

molecular imaging. The integration of this 

breadth of expertise is still in its early stages. 

• The NCI has also funded nine preICMIC planning grants 

(http://grants.nih.gov/grants/guide/rfafiles/RFA-CA-99-002.html) . The preICMIC planning grants provide time and 

funds for investigators and institutions to 

prepare themselves, organizationally and 

scientifically, to establish an ICMIC 

• Small animal models, particularly 

genetically engineered mice, are powerful 

discovery tools, but we have yet to capitalize 

fully on their potential in cancer research. 

NCI has funded five Small Animal Imaging 

Resource Programs (SAIRP) 

(http://grants.nih.gov/grants/guide/rfafiles/RFA-CA-98-023.html). This initiative 

supports activities to develop and apply a 

wide variety of imaging modalities that 

focus on functional, quantitative imaging. 

Quantitating image data for small animals 

will lead the way to quantitative methods 

that can be applied in humans. An additional 

five SAIRPs will be funded in fiscal year 

2001. 

Imaging 49 
• New drug discovery programs are 

producing an increasing number of 

molecules for investigation, in turn 

stimulating a need for research that 

integrates imaging techniques into 

preclinical and clinical studies to assess 

newly developed therapeutic agents. NCI 

has set aside funding for the development 

and application of labeled therapeutic agents 

as compounds for imaging studies and 

imaging agents that serve as metabolic 

markers of response to newly developed 

therapeutic agents. The Development of 

Clinical Imaging Drugs and Enhancers 

(DCIDE)(http://cancer.gov/bip/dcide.htm) 

program will facilitate the development of 

novel imaging agents in preclinical 

development. A detailed overview of the 

newly approved DCIDE program will be 

presented at a future date in Academic 

Radiology. 

Cellular and Molecular Imaging in 

Cancer: Meeting the Goals 

To ensure that the initially defined goals for 

cellular and molecular imaging are met and 

completed in future years, the NCI has set 

forth in the 2001 Bypass Budget specific 

priorities and initiatives. These include: 

1. Accelerate development of clinically 

useful technologies for detecting malignant 

and precancerous cells and for visualizing 

their functional characteristics. 

• Expand the number of In-Vivo 

Cellular and Molecular Imaging Centers 

(ICMIC) in 2001, 2003, and 2004. 

• Expand the Small Animal Imaging 

Resources Program (SAIRP) to improve 

access to researchers testing new approaches 

to diagnosis, treatment, and prevention in 

animal models of cancer. NCI will foster 

collaborations between this program and the 

Mouse Models of Human Cancers 

Consortium (MMHCC). 

• Support multidisciplinary centers of 

expertise to develop optical technologies and 

perform clinical feasibility tests of 

instruments able to visualize epithelial tissue 

at risk for common cancers and recognize 

the optical signatures of precancerous 

abnormalities. This often involves 

molecularly oriented techniques. 

2. Develop, synthesize, validate, and 

distribute to the research community novel 

imaging agents. 

• Expand a program similar to NCI’s 

Rapid Access to Intervention Development 

(RAID) initiative (which is designed to 

accelerate the movement of novel 

interventions from the laboratory to the 

clinic) specifically for imaging agent 

development. The Development of Clinical 

Imaging Drugs and Enhancers (DCIDE) 

program (http://cancer.gov/bip/dcide.htm) 

will facilitate and promote preclinical 

development and validation of important 

imaging agents and ligands. NCI will, on a 

competitive basis, synthesize, test, and 

distribute probes that image the 

physiological and functional status of tumor 

tissue in the human body. The DCIDE 

program will be described in detail in a 

future issue of Academic Radiology. 

• Establish a publicly available 

database of agents available to the research 

community, together with information on 

their properties. 

3. Expand and improve clinical studies of 

molecularly based imaging modalities and 

image-guided interventions. 

4. Integrate molecular and functional 

imaging technologies into drug development 

and early clinical trials 

(http://cancer.gov/bip/concepts.htm - c4). 

• Support the development of in-vivo 

and molecular clinical imaging research 

tools for assessing the biological effect of 

cancer drugs on their intended target or 

pathway. 

• With this continued investment in 

the future of imaging research, it will soon 

50 Report of the Brain Tumor Progress Review Group 
be possible to apply the techniques 

developed to image novel molecular targets, 

specific genetic pathways, signal 

transduction, cell cycle alterations, 

angiogenesis, apoptosis, and numerous other 

biologically relevant processes known to 

occur in cancer in routine clinical practice. 

Cellular and Molecular Imaging in 

Cancer: The State of the Art 

It is likely that the NCI goals and visions of 

cellular and molecular imaging in cancer 

research and patient care will be met. It is 

gratifying to note that the power of imaging 

with PET, nuclear medicine techniques, 

MRS, ultrasound, CT, optical imaging, and 

other techniques is being recognized and 

these techniques are becoming available in 

routine clinical practice. These modalities 

will allow for the molecular, functional, 

biochemical, and physiologic assessment of 

important aspects of malignancy. Many of 

these imaging techniques are already 

beginning to show their potential power in 

the management of the patient with cancer. 

With the continued advancements that are 

hoped to occur, imaging will assume a 

critical and essential role in the basic 

scientific understanding, diagnosis, staging, 

and monitoring of cancer. 

In addition to the initiatives already in place 

and listed above, the resources required to 

address the challenges and opportunities for 

using imaging technologies in the study of 

brain tumor development and their treatment 

will require targeted funding in each of the 

areas detailed above. In addition, it is 

recommended that funds be provided for 

training in the areas of image analysis, tracer 

development, image methods development, 

and informatics systems. Funding should 

also be developed in a way that mandates 

integration of data across modalities, spatialtemporal domains, subjects, trials and 

species. This will require appropriate 

funding for the development of atlases and 

databases in which such complex and largescale data sets (from patient outcomes to 

gene chip arrays) can be organized, archived, 

accessed, and distributed. Funding agencies 

should also provide opportunities for 

investigators to meet across disciplines to 

develop standards for communicating such 

information and to alter the sociological 

outlook of investigators from one of 

isolation and territoriality to integration and 

sharing. Finally, specific emphasis should be 

placed on funding programs that develop 

tools to standardize and normalize image 

acquisition across investigational sites and 

to develop core, quantitative analysis and 

feature extraction algorithms for the postprocessing and distribution of imaging 

studies acquired from all imaging modalities 

in patients with brain tumors. 

Imaging 51 
Tumor Immunology 

Co-Chairs: Darell D. Bigner, M.D., Ph.D., and Richard M. Ransohoff, M.D. 

Participants: 

David Ashley 

E. Antonio Chiocca 

Glenn Dranoff 

Carol Krutchko 

Andreas Kurtz 

Lois Lampson 

Linda M. Liau 

Sherie Morrison 

David Parkinson 

Sam D. Rabkin 

Tom Rozman 

John H. Sampson 

Diane Traynor 

Carol Wikstrand 

Han Ying 

Richard Youle 

Jeanne Young 

John S. Yu 

STATEMENT OF THE PROBLEM 

There is a current lack of basic information 

concerning the functioning of the immune 

system within the central nervous system 

(CNS). It is imperative to narrow this 

sizeable gap in understanding of the 

interaction of these two systems in order to 

gain insight into the pathogenesis of primary 

brain tumors and the immunotherapeutic 

approaches that are most likely to produce 

successful outcomes in their treatment. 

For broad purposes of discussion in this 

report, tumor immunotherapy may be 

considered to be both cell mediated (Tlymphocyte cell) and antibody mediated. 

Both types of immunotherapy are 

characterized by great specificity and low 

toxicity, as long as they are carefully 

administered. Current T-cell strategies 

involve recruiting tumor-reactive T-cells 

after exposure of autologous professional 

antigen-presenting cells to tumor antigens, 

and reinfusing them. Tumor-specific 

antibodies or their smaller fragments, such 

as single-fragment chains, are generated by 

hybrid technology from conventional or 

double-knockout/double-transgenic mice or 

from phage display systems. Antibodies may 

kill tumor cells in “unarmed” fashion or by 

directing drugs, radionuclides, or toxins to 

tumor cells. 

CHALLENGES AND QUESTIONS 

The areas in which further information 

would be most beneficial include the 

following: 

• Identifying the antigen-presenting 

cell(s) (APC) of the CNS: For 

example, is there a CNS APC, or must 

we use APCs such as peripheral 

immune system dendritic cells? 

• Determining the extent and pattern of 

the lymphoid drainage pathways of the 

CNS: Evidence for lymphoid drainage 

pathways in the CNS has been found in 

animals, but little is known of their 

existence or characteristics in humans. 

• Elucidating the mechanisms or 

pathways by which marrow-derived 

immunocompetent cells traffic to the 

CNS: Chemokines, which are 

important in this process, are produced 

by resident neural cells, including 

glioma cells, and are essential for 

leukocyte recruitment to the normal 

and inflamed CNS. Chemokines also 

provide growth regulatory signals for 

glia during development and neoplasia 

and thus may play a complex role in 

the response of the CNS host organ to 

tumor. 

• Identifying the important immune 

effector mechanisms in the CNS, both 

cell mediated and antibody mediated, 

and complement 

52 Report of the Brain Tumor Progress Review Group 
• Identifying the antigens expressed on 

CNS tumors that also have 

encephalitogenic potential: Powerful 

immune responses underlie the 

relatively rare paraneoplastic 

syndromes, and immunotherapy targets 

potentially exist inside the CNS. 

However, unless directed 

appropriately, antigenic therapy bears 

the risk of extensive CNS destruction. 

• Further understanding of the 

mechanisms by which CNS tissues and 

CNS tumors exert both local and 

systemic immunosuppressive effects: 

Although brain tumor–related 

immunosuppression is not severe 

enough to cause opportunistic 

infections, these effects may interfere 

with cell- and antibody-mediated 

tumor immune mechanisms. 

BARRIERS 

The development of predictive large and 

small animal models of primary CNS tumors 

is of great importance in the application of 

immunotherapy to primary brain tumors. 

Animal models have yielded disconcertingly 

little cross-species applicability in the 

treatment of brain tumors in the past; for 

example, the pharmaceuticals that have been 

found to be effective in mice with 

experimental allergic encephalomyelitis, a 

murine model of multiple sclerosis, have not 

proven effective in human trials. There are 

currently no predictive animal models for 

immunotherapy. However, the development 

of genetically modified mice provides 

promise of the ability to extrapolate the 

findings of mouse studies more effectively 

to human applications. 

In mice, such models could be used to 

address critical problems, including the 

effector mechanisms by which immune 

responses to tumors can eliminate neoplastic 

cells. The creation of animal models of the 

paraneoplastic, immunologically mediated 

disorders of the CNS would also be 

advantageous for the examination of 

immunologic effector mechanisms. 

Another barrier to optimal progress in tumor 

immunology is the lack of methodological 

consistency. Different immunotherapy 

groups use differing immunization 

strategies, thus diminishing the ability of 

clinicians to reach significant conclusions by 

comparing their results across trials. For 

example, at least four institutions are 

currently involved in dendritic cell trials, but 

each group uses a different method of cell 

preparation. Another area in which 

establishing a consistent methodology would 

be beneficial is the key investigative 

analyses of the immune responses of patients 

involved in clinical trials. Finally, although 

generation of CTL responses is not generally 

considered a gold standard for therapeutic 

success, it is an important technical outcome 

measure and should be determined in similar 

fashion by all investigators. Such is currently 

not the case. 

There is a strongly felt need among 

immunotherapists that some outcome 

measures short of survival would be 

advantageous in evaluating investigative 

therapies rapidly and efficiently. Possible 

outcome measures could involve welldefined immunological endpoints and 

determination of toxicity or demonstration 

that the desired immune response has indeed 

been elicited. 

An additional barrier to obtaining the 

maximal benefit from clinical trials of 

immunotherapy has been the lack of an 

optimal data set from all patients entered in 

those trials. For example, stratification for 

the degree of pre-treatment immunological 

suppression is not always done. It has been 

suggested that future initiatives should 

include, for instance, a complete proteomic 

analysis of the components of acid-washed 

membrane preparations used to pulse 

Tumor Immunology 53 
dendritic cells, and ultimately molecular 

knowledge of each antigen employed. 

A common theme of the preceding 

paragraphs, following but by no means 

eclipsing the discussion of animal models, is 

the need for consistency: in immunization 

strategies, in a consensus on the use of 

outcome models short of survival, and in 

obtaining the most complete and clinicallyinformative data set possible from patients 

in clinical trials. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Among the areas of tumor immunology 

considered to be of greatest value and 

interest in the development of brain tumor 

immunotherapy, the following topics were 

selected by a consensus of the PRG 

participants as most deserving of research 

focus and funding: 

Priority 1: 

Develop techniques of antigen 

identification, resulting in a readily 

accessible source of information on the 

genes and gene products that produce 

antigens. 

A preliminary database already exists 

containing information characterizing genes 

that are differentially expressed in tumor 

cells as opposed to those typically found in 

non-neoplastic tissue. 

• To accomplish antigen identification, 

researchers will require highthroughput screens to define the 

antigens recognizable by T-cells. 

• Similarly, high-throughput screens are 

needed to permit the identification of 

cell surface antigens and antigens 

located in the extracellular matrix, 

which may be approachable by 

antibody-targeted therapy. 

Priority 2: 

Characterize both CNS and systemic 

immune responses in patients with brain 

tumors. 

Protective (tumor-destructive) responses are 

poorly understood. Deleterious reactions are 

frequently generated by interactions between 

neoplastic cells and the immune system 

response apparatus. These interactions are 

capable of generating tumor growth factors, 

angiogenic factors, and immunosuppressive 

components. 

Tumor-associated immunosuppression is 

little understood, yet clinicians must learn to 

control this mechanism and develop means 

of dealing with it. Helpful investigatory 

areas would include characterization of the 

underlying mechanisms, implications for the 

natural history of the tumor, and 

consequences of the immunosuppressive 

reaction for the immunotherapy of the 

tumor. 

Priority 3: 

Consider the problems and challenges 

posed by patient and tumor 

heterogeneity. 

Individual patients are heterogeneous, for 

both genetic (e.g., human leukocyte antigen) 

and epigenetic reasons, in their abilities to 

respond to immunotherapy. Tumors are 

heterogeneous with regard to antigen 

expression. Heterogeneity needs to be 

understood in each tumor so that as many as 

three or four individual molecular antigenic 

species may be targeted at one time. Target 

cells also display heterogeneity with regard 

to intracellular components that confer 

susceptibility to enzyme- or Fas-mediated 

programmed cell death. 

54 Report of the Brain Tumor Progress Review Group 
RESOURCES NEEDED 

• Brain Tumor Clinical Consortia for 

expediting chemotherapy and radiation 

therapy are funded by the National 

Cancer Institute (NCI) and are 

productive. Similar clinical consortia 

for immunotherapy, especially for 

Phase I and II trials, are needed to 

expedite and standardize approaches. 

There are enough institutions (five or 

six) ready to form the critical mass 

necessary for such consortia. Human 

trials are more important than animal 

studies. For example, cytokines are 

species specific, and human cytokines 

can be evaluated only in primate 

systems. 

• Dedicated support from the National 

Institute of Neurological Disorders and 

Stroke (NINDS) to understand basic 

mechanisms of immune responses in 

the CNS is important for demyelinating 

and viral diseases as well as for brain 

tumors. 

• The voluminous data from genomic 

differential displays have revealed 

many expressed genes in brain tumors 

not present in normal CNS. Before 

such findings can be used for 

immunotherapy, high-throughput 

screening must be developed and used 

to identify linear peptide T-cell and 

conformational antibody-targeted 

antigens. Workshops may be necessary 

for implementation. 

• The NCI Rapid Access to Intervention 

Technology (RAID) program for 

biologics should be expanded to 

include NINDS investigators. 

• Brain Tumor Immunotherapy Center 

Grants, Program Project Grants, and 

SPORES should be solicited by NCI 

and NINDS. 

• Centralized transgenic and scientific 

model shared resources are needed. An 

especially important animal need is the 

availability of double-deletion/doubletransgenic mice with murine 

immunoglobulin genes replaced with 

human immunoglobulin genes. Such 

mice can be used for production of 

fully human monoclonal antibodies for 

repetitive administration to patients 

with brain tumors and other cancers. 

• Clinical trial support mechanisms are 

needed to cover the cost of research 

activities, including immunological 

assays, scanning, and autopsies, not 

covered by third-party payers. The 

National Institute on Aging 

successfully worked with investigators 

and advocates in dementia to obtain 

funding for research autopsies. 

Advocates should encourage federal 

legislation to provide a payment 

mechanism for research autopsies. 

• Accessible proteomic facilities are 

needed to provide molecular 

characterization of antigens now 

presented in unpurified, crude form, 

such as cell lysates. 

Tumor Immunology 55 
Experimental Models for Brain Tumor 

Co-chairs: Eric C. Holland, M.D., Ph.D., and Robert L. Martuza, M.D. 

Participants: 

David Ashley 

Michael Berens 

Tom Curran 

Ronald A. DePinho 

Glenn Dranoff 

Henry Friedman 

Mark A. Israel 

Andreas Kurtz 

Linda M. Liau 

Luis Parada 

David H. Rowitch 

Evan Snyder 

Carol Wikstrand 

STATEMENT OF THE PROBLEM 

Models are central to making the transition 

from scientific concepts to understanding the 

reality of a tumor in a person. They may be 

used for therapeutic screens, in preclinical 

trials, or to study the basic biology of 

tumors. Unfortunately, the available model 

systems, whether at the cellular, tissue, or 

animal level, do not accurately represent the 

biology of human brain tumors. Established 

glioma cell lines develop multiple genetic 

changes over time, so that they no longer 

reflect the biology of the tumor in the 

person. In addition, current primary tissue 

models cannot be maintained in a healthy 

condition for more than a few days. Finally, 

implantation animal models do not reflect 

the interaction between tumor and host that 

occurs in the human. 

CHALLENGES AND QUESTIONS 

Existing Models 

• Conventionally used glioma-derived 

cell lines contain genetic and gene 

expression alterations that are ill 

defined and do not necessarily reflect 

the primary tumors from which they 

were derived. Therefore, data derived 

from them may not reflect the biology, 

heterogeneity, or therapeutic response 

of the primary tumors. The scientific 

community needs better cell culture 

and tissue models that more accurately 

reflect the biology of brain tumors. 

• Traditional rodent models do not 

accurately reflect the growth, invasion, 

histology, gene expression profiling, 

vasculature, and stromal interactions of 

various intracranial tumors. 

• No genetically defined brain tumor 

models exist in species other than in 

laboratory mice. Such animal models 

may offer additional insights into the 

biology of specific brain tumor types or 

may allow the testing of specific 

therapeutic modalities that is not 

possible in mice. 

Future Models 

• The gene expression profiles, 

controlling elements, pathways, and 

cells of origin for brain tumors remain 

largely unknown. 

• Molecular reagents, such as tissuespecific promoters and enhancers, to 

create genetically accurate models of 

brain tumors are lacking. Further, it is 

necessary to identify to oncogenes and 

tumor suppressors, as well as to 

develop the technology needed to 

combine alterations in the appropriate 

cell types. 

• There are no adequate mechanisms to 

correlate genetic alterations in mouse 

56 Report of the Brain Tumor Progress Review Group 
tumors with their proposed human 

counterparts. 

• There are no readily available and 

affordable noninvasive techniques to 

allow investigators to measure changes 

in tumor volume, growth pattern, gene 

expression, and other biological 

parameters of interest. 

Model Availability 

• Investigators who are not directly 

involved in the production of animal 

models lack easy and affordable access 

to these models. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Develop tissue and cell culture systems 

that replicate the biology of human brain 

tumors more adequately than do the 

currently available immortalized cell 

lines. 

Specifically, there is a need to develop and 

validate primary tissue culture systems such 

as spheroids, brain slice cultures, primary 

cell cultures, and genetically defined 

immortalized cells, including stem cells. 

These systems need to be characterized as to 

their similarity to the brain tumors that they 

are designed to model. 

Priority 2: 

Create genetically accurate animal models 

for brain tumors. 

An essential first step is to define and 

develop reagents, including tissue-specific 

promoters and enhancers, as well as to 

expand our capabilities for readily 

combining multiple genetic alterations in 

specific cell types. 

The development of accurate mouse models 

is very important. In addition, the 

development of genetically defined brain 

tumor models in other species should be 

encouraged. Such species may include 

smaller animals, such as Drosophila or fish, 

as well as larger animals, such as pigs and 

dogs. These have the potential to be used to 

further understanding of the biology of the 

disease. In particular, the anatomical spatial 

dimensions of larger animal models may 

better allow for the testing of surgical 

interventions and novel delivery techniques. 

Priority 3: 

Generate methods to validate, compare, 

and contrast the animal model with its 

proposed human counterpart. 

These methods should include standard 

methods such as histology, magnetic 

resonance imaging, anatomical imaging, and 

therapeutic response, as well as gene 

expression and genomic profiling. This will 

require the development of mouse arrays 

from the mouse counterparts to the human 

BTGAP sequences. In addition, 

methodologies such as BAC arrays or SKY 

analysis will be required to assess the 

acquired genomic alterations. Adequate 

bioinformatics support will be required in 

order to analyze these data. 

Further development and use of noninvasive 

technology is necessary to measure aspects 

of tumor biology in these animal models. 

Specifically, there is a need for image 

analysis of gene expression, vascularity, 

tumor size, and invasiveness, and for other 

noninvasive techniques, such as serum or 

urine surrogate markers. These may require 

the generation of specific, genetically altered 

reporter mice. 

Experimental Models for Brain Tumor 57 
Priority 4: 

Improve access to and make available at 

reasonable cost to investigators: 

• The reagents needed to create new 

animal models of brain tumors 

• Sophisticated technologies used to 

evaluate and validate those models 

• The animal models themselves 

Expression cDNA microarray and BAC 

array technologies should be made available 

for analysis of these murine-derived tumors. 

Currently, access to these technologies is not 

readily available to all groups of 

investigators whose important scientific 

questions require these animal models. 

Moreover, investigators who have developed 

these animal models do not have the 

resources needed to provide and widely 

distribute them. 

RESOURCES NEEDED 

• Because of the lack of adequate cell, 

tissue, and animal model systems that 

reflect human brain tumors, and 

because grants to develop model 

systems traditionally have not been 

funded by the National Institutes of 

Health, a mechanism must be created 

specifically to fund the development 

and validation of model systems that 

more accurately reflect the biology of 

brain neoplasms. Although the 

National Cancer Institute (NCI) Mouse 

Models for Human Cancer Consortium 

(MMHCC) has been established to 

fund development of mouse cancer 

models in general, the National 

Institute of Neurological Disorders and 

Stroke (NINDS) needs to emphasize 

and coordinate with the NCI for the 

development of additional mouse 

models of the various brain tumors not 

addressed through the MMHCC and of 

models in other animals. 

• Resources need to be allocated for the 

generation of cDNA microarrays based 

on the mouse equivalent of the human 

BTGAP sequences. 

• A mechanism must be created to 

ensure affordable access to the reagents 

and models listed above to 

investigators. Furthermore, the NCI 

and NINDS should provide resources 

to establish a consortium of brain 

tumor modeling laboratories for the 

purpose of testing novel therapies. 

58 Report of the Brain Tumor Progress Review Group 
Neurobiology: Cell Migration and Dispersal 

Co-chairs: James Goldman, M.D., Ph.D., and Rolando Del Maestro, M.D., Ph.D. 

Participants: 

Candece Gladson 

Susan Hockfield 

Lois Lampson 

Marla B. Luskin 

Robert H. Miller 

Maiken Nedergaard 

Jasti S. Rao 

Sandra Rempel 

Steve Rosenfeld 

John H. Sampson 

Harald Sontheimer 

Richard Vallee 

Jeanne Young 

STATEMENT OF THE PROBLEM 

A hallmark of primary neuroectodermal 

neoplasms is their infiltrative nature. By the 

time most such tumors are diagnosed, cells 

have spread beyond the neoplasm’s 

identifiable mass and into surrounding 

tissues. These dispersed cells may contribute 

to tumor recurrence in situations in which 

the primary site can be controlled by surgery 

or other therapies. Rather little is known 

about the process of this spread. 

The breakout group on Neurobiology: Cell 

Migration and Dispersal discussed the 

nomenclature used to describe cell 

movement from tumor masses into brain 

parenchyma. To avoid some implications of 

terms such as migration, invasion, and 

infiltration, it was agreed to use the word 

dispersal to describe the movement of tumor 

cells through the central nervous system 

(CNS). 

CHALLENGES AND QUESTIONS 

• The need to understand brain tumor 

dispersal through the CNS 

• The need for more information on how 

tumor cells interact with normal 

cellular constituents of the brain. 

Emphasis should be placed on 

developing new models for studying 

tumor cell dispersal and tumor-CNS 

interactions. 

• The need to consider how further 

knowledge of the first two phenomena 

could result in new therapies. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Define the molecular constituents 

required for dispersal. 

Although redundancy in motility-based 

genes may make it problematic to isolate 

specific targets, there is evidence that cellspecific isoforms exist for some of these 

proteins. It would be valuable, therefore, to 

identify and determine the function of gene 

products that regulate motility in 

neuroectodermal tumors. The molecules 

include possible tumor- or tumor-type 

specific motors and cytoskeletal proteins; 

small GTPases that regulate interactions 

between external signals and internal 

cytoskeletal organization; cell surface 

receptors involved in cell migration, 

including those that may mediate start or 

stop signals or maintain cell polarity; 

components of extracellular matrix, 

including proteases involved in remodeling 

extracellular matrix molecules as cells 

Neurobiology: Cell Migration and Dispersal 59 
migrate; ion channels that may allow 

changes in cell shape or cell volume during 

migration; G protein–coupled receptors; and 

the extracellular matrix molecules produced 

by both tumor and CNS. 

Resources needed: 

• Use DNA chip technology to examine 

appropriate tumor cell types, preferably 

freshly isolated tumor cells rather than 

tumor cell lines. It may be worthwhile 

to search for differences among tumor 

types that display characteristic and 

different migratory patterns (e.g., 

juvenile pilocytic astrocytomas through 

white matter, oligodendrogliomas 

through white matter and into cortex, 

and medulloblastomas). 

• This kind of search should also be 

carried out for normal glial and 

neuronal progenitors, because little is 

known about the specific molecular 

mechanisms underlying migration and 

because normal and tumor cells 

probably share many common 

regulatory mechanisms. 

Priority 2: 

Examine how tumor cells interact with 

the brain’s normal cellular constituents. 

Little is known about how tumor cells 

interact with normal neurons and glia. 

Several kinds of interactions are worthy of 

investigation, including gap-junction 

formation between tumors and normal 

astrocytes, altered potassium or 

neurotransmitter (glutamate) buffering 

produced by tumor cells in proximity to 

neurons, synaptic disruption, interactions 

between migrating tumor cells and the CNS 

extracellular matrix, and interactions with 

the immune system (Do tumors activate 

resting microglia? If so, how? Do tumors, 

which express a variety of cytokines, attract 

lymphocytes into the CNS?) 

Emphasis should be placed on examining 

tumor-CNS interactions in appropriate in 

vivo and in vitro tumor models. It is 

important to design assays that determine the 

functional consequences of these 

interactions and whether the perturbations 

are reversible. Studies that integrate the 

anatomy and physiology of tumor-CNS 

interactions should receive highest priority. 

Resources needed: 

• New models are needed for studying 

tumor cell dispersal and tumor-CNS 

interactions 

The group discussed existing models, 

including two- and three-dimensional 

models in vitro and co-culture experiments 

with tumor and normal brain, but focused on 

using existing models and on developing 

new models in which tumor cells could be 

studied moving through the normal CNS. 

This could be accomplished in brain slices 

or in whole animal models, from which 

slices could be used to examine tumor cell 

movements. These would be particularly 

useful if the models resulted in tumors 

whose cells disperse through the brain and 

are tagged to be clearly distinguishable from 

normal cells. It is hoped that such animal 

models would be freely available to 

investigators interested in tumor cell 

dispersal. 

Priority 3: 

Determine how we can best use the 

knowledge acquired through research 

described in the priorities above to define 

new therapeutic targets. 

For example, can lymphocytes be directed 

toward dispersed tumor cells? Can other 

migratory cells (progenitors) expressing 

60 Report of the Brain Tumor Progress Review Group 
t

herapeutic genes be directed toward 

dispersed tumor cells? Can chemoattractants 

be used to bring tumor cells back to the main 

tumor mass? Is there a way to stop migration 

so tumor dispersal is controlled? This may 

have the consequence of halting tumor 

spread without killing the tumor, thus turning a brain tumor into a chronic disease. 

Studies that emphasize controlling tumor 

dispersal should receive high priority. 

Interactions between cell movement and cell 

division must be carefully ascertained in 

various model systems. That is, what are the consequences of inhibiting cell motility in 

other cell functions, particularly 

proliferation? 

Resources needed: • A National Institutes of He

alth focus 

group in which researchers who study 

normal neuronal- and glial-progenitor 

migration interact with tumor 

biologists who study neoplastic cell 

movement. The two groups have a 

great deal to learn from each other, and 

such a meeting may result in beneficial 

collaborations. 

•A consortium whose members work in 

established laboratories with expertise 

in various cell migration models, to allow new molecules that may be 

useful in blocking elements of tumor 

dispersal to be efficiently screened. 

Neurobiology: Cell Migration and Dispersal 61 
Neurobiology: Progenitor Cells 

Co-Chairs: Robert H. Miller, Ph.D., and Scott Pomeroy, M.D., Ph.D. 

Participants: 

Keith L. Black 

Lester Drewes 

Howard A. Fine 

Joseph C. Gloriosa 

James E. Goldman 

Eric C. Holland 

David Kaplan 

Marla B. Luskin 

Maiken Needergaard 

Larry Pizzi 

Greg Riggins 

David H. Rowitch 

Evan Snyder 

Harald Sontheimer 

Susan L. Weiner 

STATEMENT OF THE PROBLEM 

The vertebrate central nervous system 

(CNS) is a unique tissue in terms of cell 

number and diversity. During development, 

the major classes of neural cells are derived 

from cells of the neuroepithelium. At present 

it is not known how these divergent cell 

types are specified and how they relate to 

highly heterogeneous brain tumors. There is 

also a current lack of understanding of the 

cells of origin and cell lineage associations 

for distinct tumor types. To design specific 

therapeutic approaches requires a detailed 

understanding of the signal transduction 

pathways utilized by different tumor cells in 

regulating cell fate, including cell 

proliferation and cell death and 

differentiation, as well as a comparison of 

these pathways with those utilized by normal 

neural progenitors. 

An understanding of tumor cell biology 

depends on defining interactions between 

tumor cells and their immediate neural 

environment to elucidate how the 

environment influences tumor cell behavior 

and how tumor cells influence local neural 

function. 

CHALLENGES AND QUESTIONS 

• What are the cells of origin that give 

rise to distinct brain tumor types? How 

do distinct brain tumor types correlate 

with neural progenitors in the 

developing CNS? Are distinct tumor 

types derived from: 

— Multipotent stem cells? 

— Specified progenitor cells in 

the developing CNS? 

— Specified progenitor cells in 

the adult CNS? 

— Differentiated cells in the 

adult CNS? 

• What approaches will yield a 

comprehensive molecular 

characterization of tumor and normal 

neural progenitor cells? What model 

systems are best suited to define tumor 

cell origins? Can human neural stem 

cells and their derivatives be used in 

defining tumor cell origins? 

• What extracellular and intracellular 

signaling systems regulate the fate of 

brain tumor cells? How are the 

proliferation, differentiation, and 

survival of distinct tumor subtypes 

regulated? Are signaling pathways in 

tumor cells similar to those utilized by 

normal neural cells during 

development? Can specific molecular 

targets be identified in tumor signal 

transduction pathways for therapeutic 

treatments? What are the best cellular 

models with which to address signaling 

issues? 

62 Report of the Brain Tumor Progress Review Group 
• What are the functionally significant 

cellular interactions between the 

founder cells of neural tumors and the 

local neural environment? What are the 

physiological properties of distinct 

tumor cell types? What is the influence 

of the local neural environment on 

tumor cells? How do influences of the 

immune system impinge on neural 

tumor cells? What interactions between 

the endothelium and tumor cells 

contribute to tumor expansion? What 

approaches are required to effectively 

address interactions between tumor 

cells and their environment? 

BARRIERS 

• There is extensive cellular diversity 

among neural cell types and brain 

tumor subtypes. 

• There is a lack of understanding of the 

basic biology of neural cell fate 

determination, particularly within glial 

lineages. 

• Insufficient research effort is being 

brought to bear on the cellular 

neurobiology of brain tumors. 

• The lack of interaction between 

neurobiologists and neurooncologists 

has precluded the effective translation 

of progress in basic research to brain 

tumor research. 

• There is a lack of appropriate 

molecular screening systems such as 

microchip arrays for further 

advancement of molecular 

classification and identification of 

specific signaling systems. 

• There is a lack of appropriate models 

in which to study brain tumor biology 

• There is a lack of representative cell 

lines in which to study the extrinsic 

and intrinsic signal systems that control 

normal and tumor progenitor cell fate. 

• Current tissue banks are limited, and 

their existence or mode of access is not 

obvious to non–brain tumor 

neurobiologists. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Create a detailed characterization of the 

cell of origin of different brain tumor 

types. 

This requires a clear definition of the 

cellular and molecular characteristics of 

neural cells during development. Basic 

biologic studies suggest that tumors might 

arise from multipotential stem cells, 

specified progenitor cells in the developing 

or adult central nervous system (CNS), or 

dedifferentiation of mature neural cells. To 

address this issue requires the following: 

• Identification of new cell-surface 

markers and specific receptors for 

extracellular ligands 

• Identification of lineage- and stagespecific transcription factors and other 

intracellular signaling molecules 

• Application of these markers for 

molecular classification of brain 

tumors such that relationships between 

cells at distinct developmental stages 

of normal development and tumors 

become apparent 

• Studies of tumor cellular biology 

provide a potentially important 

approach to defining molecular targets 

that could lead to further understanding 

of normal neural development 

• Analyses of glial development and 

definition of glial progenitors in the 

vertebrate CNS. This reflects a high 

incidence of glial tumors and the 

relatively low emphasis on glial 

progenitor research by the 

neurobiology community. 

Neurobiology: Progenitor Cells 63 
Resources needed: 

To define cellular origins of different brain 

tumor subtypes, the following resources are 

required: 

• Model development: There is a 

shortage of effective cell-based 

models. Present emphasis is on mouse 

and rat models, but the use of other 

animals, including zebrafish, dogs, and 

others should not be excluded. New in 

vitro models also need to be 

developed. Emphasis could be placed 

on human stem cells/progenitor cells in 

this system, since species differences 

may exist. Progress in this area would 

be enhanced through the development 

and analyses of multiple model 

systems rather than a focus on a single 

or restricted number of models or cell 

lines. 

• Development of microarrays to 

generate genetic, molecular, and 

biochemical information. Specifically, 

development of custom-designed 

neurodevelopment arrays are 

important. 

• Tissue banking: Wide access to such 

tissue resources is critically important. 

• Development of tissue arrays for 

further advancement of cellular 

classification 

• Development of infrastructure to 

encourage interaction between 

scientists in basic neuroscience and 

neurooncology: These should include 

the development of new funding 

mechanisms that directly allow 

interdisciplinary teams of scientist to 

address cellular issues of brain tumor 

biology. 

Priority 2: 

Develop an understanding of the 

regulation of mitogenic and antimitogenic control of tumor and normal 

neural progenitor cells. 

A thorough understanding of extracellular 

signaling systems and signal transduction 

pathways that control progression through 

the cell cycle and specific inhibitors of 

progression through the cell cycle is 

required. Studies should be directed at 

dissecting and identifying targets of cell 

growth, cell death and survival, and 

differentiation in normal and tumor 

progenitors. It seems likely that each distinct 

tumor type will utilize a different set of 

regulatory signaling pathways and share 

some common effector mechanisms. 

Comparison of regulatory signaling 

pathways will lead to enhanced 

understanding of neural tumors and the 

development of potential targets for specific 

intervention strategies. In addition, such 

studies are likely to provide molecular 

definitions of progenitor cells at critical 

developmental junctions and may 

characterize their derivative tumors. 

Resources needed: 

Defining the signaling systems involved in 

control of normal and tumor progenitor cell 

fate will require the following: 

• Additional support for basic biological 

research in defining signal transduction 

pathways in neural progenitor cells, 

with particular emphasis on glial 

progenitors 

• Facilitation of substantive interactions 

among scientists focused on normal 

developmental issues and those 

focused on glial tumor biology. 

Organization of specific workshops 

and the development of joint funding 

programs between basic and clinical 

research teams may accomplish this. 

• Development of microarrays to identify 

novel signaling pathways in distinct 

cell types. 

64 Report of the Brain Tumor Progress Review Group 
• Development of new in vivo and in 

vitro model systems in which to 

explore functional requirements for 

discrete signaling pathways. 

Specifically, given the limitation of 

cellular material from distinct tumor 

types, a need was recognized to 

develop new cell lines that more 

closely represent native tumor cells by 

using recently developed molecular 

techniques. 

Priority 3: 

Understand the interactions of brain 

tumors with their immediate neural 

environment. Studies directed at 

dissecting tumor-brain interactions 

should focus on the following areas: 

• Further characterization of the 

physiological properties of tumor cells 

and the composition of the neural 

environment are needed. The ionic 

environment and activation of distinct 

channels in tumor cells may regulate 

cell morphology, proliferation, and 

motility. A broader understanding of 

interactions of tumor cells with 

microglial cells and cells of the 

immune system is warranted. 

Developmental studies have begun to 

provide evidence that neural cells 

respond to immune cells and their 

influences in a number of ways; these 

include control of cell morphology, 

migration, and proliferation. Defining 

tumor cell responses to immunological 

influences appears timely. 

• Interactions between tumor cells and 

the local endothelium are poorly 

understood. Regulation of the bloodbrain barrier, control of vessel 

formation, and other aspects of this 

interaction require additional analyses. 

Resources Needed 

The resources required to address this 

research priority include: 

• Basic research in non-neuronal cell ion 

channel expression and function 

• Models of neovascularization in vitro 

• Identification of the distinct molecular 

properties of brain endothelium, 

perivascular astrocytes, and microglia 

• Facilitation of interactions between 

neurobiologists, brain tumor biologists, 

and immunologists through the 

development of novel interdisciplinary 

funding programs and focused 

meetings or workshops 

Neurobiology: Progenitor Cells 65 
Radiation Biology 

Co-chairs: Dennis Shrieve, M.D., Ph.D., and Philip J. Tofilon, Ph.D. 

Participants: 

C. Norman Coleman 

Brian Fuller 

Glenn Gobel 

Daphne A. Haas-Kogen 

Peter Inskip 

Larry Kun 

Frederick F. Lang, Jr. 

Bertrand Liang 

Jay Loeffler 

Lorraine Marin 

Minesh Mehta 

Raymond Mulhern 

Judith J. Ochs 

Ed Oldfield 

Libby Stevenson 

STATEMENT OF THE PROBLEM 

CLINICAL RADIORESISTANCE OF PRIMARY 

GLIAL TUMORS 

Radiation therapy is a major component of 

the treatment of many primary and 

metastatic brain tumors. Standard therapy 

for glioblastoma multiforme and other 

primary malignant astrocytomas consists of 

radiotherapy after the fullest possible 

surgical resection has been performed. 

Radiotherapy has long been known to be the 

single most active treatment for these 

tumors; doses up to about 60 Gy yield doserelated increases in survival. 

Despite this therapeutic benefit, however, in 

nearly all patients such tumors recur within 

the volume of tissue receiving high-dose 

radiation, and eventually these patients 

succumb to local disease within a median 

period of about 12 months. Attempts to 

escalate radiation doses above 60 Gy have 

not yielded a significant further advantage in 

survival, probably owing to toxicity related 

to the volumes of normal brain receiving 

doses in excess of tolerance. Conformal 

therapies (brachytherapy or radiosurgery), 

designed to “boost” the local dose, may 

allow increased survival. Even after these 

therapies, however, local failure is the rule 

and the risk of radionecrosis is extremely 

high in patients surviving for more than 6 

months. Even in cases of “microscopic 

residual disease,” these doses of radiation 

are inadequate to prevent progression of 

disease. 

In vitro studies of the inherent 

radiosensitivity of cell lines derived from 

human glioblastoma multiforme have not 

demonstrated remarkable radioresistance of 

these cells. It is highly probable that the 

“neural environment” and microenvironment 

of the in situ tumors, and not just the special 

characteristics of tumor cells in culture, 

contribute to the remarkable 

radioinsensitivity of gliomas. 

NORMAL TISSUE TOXICITY AFTER 

RADIATION 

Necrosis and Edema 

Radiation doses higher than 60 Gy may 

produce vasogenic edema and necrosis in 

some patients with glioblastoma multiforme. 

Escalation of the radiation dose above this 

level poses a significant risk of necrosis. 

These risks are greater than in patients with 

lower-grade astrocytic tumors or non-glial 

tumors, which are associated with better 

prognosis and longer survival. 

Functional Deficits 

Functional deficits in patients after 

radiotherapy are probably more common 

than is currently reported. These deficits 

include mental retardation in patients 

irradiated as infants, learning disabilities in 

66 Report of the Brain Tumor Progress Review Group 
older pediatric patients, and memory or 

cognitive deficits in adults. Whole-brain 

radiotherapy for metastatic disease can result 

in a range of neurocognitive outcomes, 

ranging from little or no deficit to full-blown 

dementia. The factors contributing to the 

development of neurocognitive deficits are 

poorly understood. These deficits have 

severe effects on quality of life for patients 

and their families. 

CHALLENGES AND QUESTIONS 

• Lack of understanding of 

mechanisms of tumor 

radioresistance and normal tissue 

toxicity—Little is known of the basic 

mechanisms by which radiation kills 

brain tumor (or other) cells. Two main 

types of cell death, however, are 

thought to be important: mitotic, or 

clonogenic, death (loss of the ability to 

divide) and apoptosis (programmed 

cell death). There is evidence that 

malignant glioma cells do not undergo 

significant apoptosis after irradiation. 

Clearly, in patients, many cells escape 

both modes of cell killing after 

radiotherapy. The “neural 

environment” appears to play an 

important role in this clinical 

radioresistance, as may 

microenvironmental factors. In 

addition, the fundamental processes 

involved in the development of normal 

tissue toxicity after radiation are not 

understood. 

• Lack of integration of neurobiology 

with radiobiology—There would be a 

great advantage to integration of basic 

and brain tumor neurobiology and 

brain tumor–related radiobiology. 

• Unavailability of appropriate 

models—Appropriate animal models 

are not available, hindering progress. 

The brain is a unique organ, and its 

milieu is crucial to the behavior of 

central nervous system tumors. Cell 

culture studies are insufficient to allow 

understanding of the interactions 

between tumor and normal tissue, 

which is key to studying the 

mechanisms of resistance and thereby 

to improving treatment. It is important 

to describe in situ the physiology of 

these tumors, which is probably 

involved to a great degree in their 

resistance. Imaging is available, but 

interactions between normal and tumor 

cells must be described and modeled. 

Better models—specifically, orthotopic 

tumor models rather than subcutaneous 

models, and practical models for 

studying late damage to the brain—are 

necessary to study these interactions. 

• Low enthusiasm for development of 

drugs or modulators of 

radiosensitivity—There is little 

enthusiasm within the pharmaceutical 

industry for the development of drugs 

or modulators of radiosensitivity for 

brain tumors. Incentives and 

encouragement for industry 

involvement in brain tumor research 

are needed. The National Cancer 

Institute (NCI) is planning to establish 

a screening program to test drugs in the 

clinic for their potential as 

radiosensitizers. 

• Inability to test new drugs designed 

to work with radiation—It is difficult 

to test new drugs designed to work 

with radiation. Combination 

development at preclinical stages 

currently does not occur. The Food and 

Drug Administration focuses on single 

agents rather than on combinedmodality therapies. Furthermore, many 

companies are apprehensive about 

studying their agents in combination 

with radiation because of concern that 

toxicity could be, or appear to be, 

Radiation Biology 67 
enhanced. This means that, owing to 

regulatory complications, 

pharmaceutical companies will not 

study combined modalities as firststrike therapies. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Overcome radioresistance of primary 

brain tumors. 

• Delineate the mechanisms of inherent 

radioresistance. 

• Define the influence of the neural 

environment on radioresistance of 

brain tumors. 

• Identify molecular targets for 

modulation of brain tumor 

radiosensitivity. 

• Develop hypothesis-driven 

combinations of radiation therapy and 

modulators to overcome resistance in 

clinical practice. 

• Develop and validate appropriate 

models. 

Priority 2: 

Overcome normal tissue toxicity 

(necrosis/edema versus functional 

deficits). 

• Delineate the molecular, cellular, and 

physiological processes leading to 

radiation-induced toxicity. 

• Define the influence of 

neurodevelopmental stage on these 

processes. 

• Delineate the interactions between 

tumor and normal cells in the 

development of radionecrosis. 

• Develop hypothesis-driven 

interventional strategies 

(radioprotection). 

• Develop and validate appropriate 

models. 

Priority 3: 

Establish clinical indicators of radiation 

response of tumor and normal tissue. 

• Develop imaging modalities to assess 

tumor response and early changes that 

are predictive of late sequelae. 

• Identify serum, cerebrospinal fluid, or 

tissue markers of tumor or normal 

tissue response. 

• Develop methods of target 

“credentialing”—identification of 

target molecules, evidence of 

modification of the target molecule, 

and measurement of desired effect. 

• Develop high-throughput techniques to 

assess the efficacy of modulators of 

radiosensitivity (e.g., microarray 

technologies). 

• Establish the use of clinical correlates 

to validate preclinical studies. 

• Develop predictors of sensitivity 

(tumor versus normal tissue). 

RESOURCES NEEDED 

• NCI program for the development of 

drugs, sensitizers, and/or modulators of 

radiosensitivity 

• Ability to test drugs in combination 

with radiation 

• NCI-sponsored workshop bringing 

together neurobiologists and 

radiobiologists to discuss strategies for 

investigating brain tumor 

radioresistance and radiation-related 

toxicity 

68 Report of the Brain Tumor Progress Review Group 
Treatment

Co-Chairs: Howard Fine, M.D., and Larry E. Kun, M.D. 

Participants: 

Mitchel Berger 

Joseph C. Gloriosa 

Stuart A. Grossman 

Alison Hannah 

Peter T.C. Ho 

William G. Kaelin, Jr. 

David Kaplan 

Kathleen Lamborn 

Bertrand Liang 

Dennis C. Shrieve 

Malcolm Smith 

Philip J. Tofilon 

Diane Traynor 

Michael Walker 

Roy S. Wu 

Mark Yarborough 

John S. Yu 

W. K. Alfred Yung 

BACKGROUND: STATUS OF THE 

FIELD 

Surgery 

The tremendous evolution in surgical 

capabilities of recent decades has been 

driven by technology. The advantage of 

maximal resection has been documented in 

most primary central nervous system (CNS) 

tumor systems. At present, the state of the 

art in treatment for brain tumors is the 

incorporation of preoperative imaging, both 

metabolic and functional, with image-guided 

surgical techniques. For example, 

“navigation” technology allows imaging in a 

patient by using external landmarks before 

surgery, and during surgery, the surgeon is 

guided to the lesion and can appreciate its 

extent based on the preoperative image set. 

The newest technologies provide 

intraoperative imaging, allowing the 

neurosurgeon to realign the threedimensional image set during surgery, 

further enhancing safe maximal resection. 

Surgery can also be important in local drug 

delivery, including the strategic placement 

of catheters to deliver small molecules. 

Careful and consistent mapping of tumor 

specimens allows coordination with 

imaging, drug delivery, and 

cellular/molecular correlates of disease 

characteristics and therapeutic response. 

Radiation Oncology 

Technology has also driven the field of 

radiation oncology. Radiation therapy has 

proven efficacy in many common tumor 

histiotypes. Trials in malignant gliomas in 

particular have provided opportunities to test 

altered fractionation and three-dimensional, 

image-guided delivery (including conformal 

photon irradiation, radiosurgery, and 

brachytherapy) to achieve substantial dose 

escalation. Unfortunately, however, there are 

few data encouraging additional 

explorations of dose escalation with 

radiation therapy alone for these inherently 

resistant tumors. Further studies of enhanced 

radiation dose are ongoing in other 

histiotypes (e.g., low-grade gliomas, and 

ependymomas). 

Interactions of radiation with 

pharmacological and biological agents 

represents an important area for further 

development. Understanding ways to 

increase tumor response and potentially to 

limit normal tissue toxicities requires 

additional laboratory and clinical testing. 

Explorations of genetic radiosensitization 

Treatment 69 
offer exciting research opportunities in the 

malignant gliomas. 

In pediatric tumors, trials of restricted 

volumes of radiation therapy and dose 

reductions defined by response to 

chemotherapy seek to improve the 

therapeutic ratio in tumor types with known 

radioresponsiveness (e.g., medulloblastoma, 

other embryonal tumors, low-grade gliomas, 

intracranial germ cell tumors). Exquisite 

localization of radiation volume in 

ependymomas is the basis for ongoing and 

planned trials even in very young children. 

Image definition of tumor extent is 

important in guiding restricted radiation 

therapy volumes; better assessments of 

tumor volumes and margins are needed. 

Chemotherapy 

Chemotherapy has had a significant impact 

on the treatment of selected CNS tumors, 

such as primary CNS lymphomas, anaplastic 

oligodendrogliomas, and pediatric 

embryonal tumors. Nevertheless, the exact 

drug regimen, timing, and duration of 

treatment remain areas of uncertainty. 

Despite the clear benefits for these selective 

tumor types, the role of standard 

chemotherapy is limited for the majority of 

primary CNS tumors, particularly tumors of 

the astrocytic lineage. Identification of the 

role of chemotherapy has been hampered by 

relatively small numbers of many brain 

tumors other than glioblastoma multiforme, 

making large randomized trials problematic, 

and by the apparent poor responsiveness of 

glioblastoma multiforme to cytotoxic 

chemotherapy. 

STATEMENT OF THE PROBLEM 

The main problems in brain tumor treatment 

research listed below are addressed in detail 

in the following section (see “Challenges 

and Questions”). 

• There are few active therapeutic 

approaches or agents for the treatment 

of brain tumors. 

• There are no adequate or reliable 

preclinical screening systems. 

• Few new agents are marked for CNS 

tumor development. 

• There is little understanding of drugradiation interactions in normal CNS 

tissue. 

CHALLENGES AND QUESTIONS 

Few Active Therapeutic Approaches or 

Agents for the Treatment of Brain 

Tumors 

Generally, there have been few significant 

advances in the treatment of malignant 

gliomas over the last two decades. 

Difficulties in identifying effective 

approaches include heterogeneity of tumor 

types, the rarity of some tumors, and relative 

difficulties in accruing adult patients to 

clinical trials. All of these problems result in 

small patient populations for clinical study. 

There are a myriad of biological reasons for 

the ineffectiveness of most current 

chemotherapeutic agents. These include 

inconsistent drug delivery secondary to 

issues related to the blood-brain and bloodtumor barriers, tumor hypoxia, intrinsic drug 

resistance, and acquired drug resistance 

through the variable exposure of tumor cells 

to different concentrations of delivered drug 

as a result of problems with drug delivery. 

The “new biology” has led to the 

identification of a number of new signaling 

pathways that appear to be important for 

gliomagenesis, and with their identification 

has come the creation of a number of new 

and exciting molecular inhibitors of those 

pathways that appear to represent exciting 

therapeutic opportunities. There is 

significant concern, however, that the 

current drug development process, from 

70 Report of the Brain Tumor Progress Review Group 
preclinical screening to clinical trial design, 

patient accrual, and endpoint assessment, 

may be suboptimal for studying newer 

cytostatic agents for brain tumors. As a 

result of this concern, there is reluctance 

from private industry (the source of the 

majority of the newer anti-tumor agents) to 

invest resources into exploring the utility of 

these agents in patients with brain tumors. 

No Adequate or Reliable Preclinical 

Screening Systems 

Preclinical screening of potential agents is 

currently time consuming and inefficient. 

Spontaneously occurring brain tumor animal 

models are not available at present, and 

there is a growing belief that currently 

utilized xenograft models do not accurately 

reproduce the biology of human tumors and 

therefore are generally nonpredictive for 

identifying active clinical agents. Therefore, 

the routine use of these models for screening 

agents for clinical development not only 

may have allowed inactive agents to enter 

clinical trials in the past, but may have 

inadvertently excluded potentially active 

drugs from ever having been evaluated 

clinically. This problem has become 

increasingly more important as the number 

of rationally designed agents with cytostatic 

rather than cytotoxic mechanisms of action 

are being developed (e.g. anti-angiogenic, 

differentiating, anti-invasion agents). Such 

agents can be adequately tested only in vivo, 

making the lack of reliable tumor models a 

major obstacle for preclinical development. 

Clearly reliable in vitro and/or tissue 

surrogate markers and/or assays of 

biological activity would be very helpful for 

the preclinical and clinical development of 

these agents (see “Few New Agents for CNS 

Tumor Development”). Coupled with the 

establishment of biological endpoints 

correlated with survival, improvements in 

preclinical screening may lead to innovative 

clinical trial designs, and ultimately the 

entire field of therapeutic development for 

brain tumors could move forward quickly 

and effectively. 

Few New Agents Marked for CNS Tumor 

Development 

Novel therapeutic development for CNS 

tumors is modest, and progress has been 

meager. Despite the exciting advances made 

in the identification of potentially active, 

selective, rationally designed anti-cancer 

agents, there has been significant reluctance 

on the part of the pharmaceutical industry to 

move these agents into the brain tumor 

population. The reason for this reluctance 

relates to the inherent characteristics of brain 

tumors and of patients with these tumors, 

which make them problematic as the focus 

of industry research. Examples include 

difficulties quantifying toxicities in patients 

with brain tumors, the altered pharmacology 

of many agents secondary to induction or 

inhibition of the hepatic P450 cytochrome 

system from concurrent administration of 

anti-epileptic agents, the heterogeneity of the 

patient population (particularly as it relates 

to heterogeneity of tumors), modest numbers 

of patients, and slow patient accrual, 

although this last issue has been addressed in 

part by the brain tumor consortia. 

Low Rate of Patient Accrual to Clinical 

Trials 

Patient accrual into clinical trials in general 

is lacking: less than 10% of adult patients 

with brain tumors enter clinical trials. Ways 

should be investigated to systematically 

increase adult patient accrual to trials. Even 

though there are at present few novel 

approaches that warrant large-scale Phase III 

trials, the infrastructure for speedy accrual 

needs to be in place in order to expedite 

testing when new agents appear promising in 

pilot studies. In addition, determining groups 

of molecularly homogeneous tumors would 

allow for more, and more effective, clinical 

trials. 

Treatment 71 
Improvements in “response” criteria are 

needed. To advance the field of novel 

therapeutic agents for brain tumors, it will 

be necessary to identify and validate 

meaningful biological endpoints for 

evaluating novel therapies. There continues 

to be significant discussion within the 

neurooncology and neuroradiology 

community as to the appropriate criteria for 

measuring radiographic tumor “response.” 

This discussion arises from the realization 

that abnormalities detected by magnetic 

resonance imaging and computed 

tomography and associated with tumors may 

be the result of pathophysiological processes 

other than the tumor mass itself. These 

abnormalities include treatment-related 

effects (e.g., radiation necrosis), cerebral 

edema, inflammation, and postsurgical 

changes. Routine criteria for measuring 

perpendicular diameters may be limited in 

reliability and accuracy by the fact that brain 

tumors often grow as irregular, asymmetrical 

processes in three dimensions, and by 

variability in head positioning in sequential 

imaging studies. The problem is further 

compounded by the realization that many of 

the novel agents entering clinical trials will 

not necessarily have cytotoxic mechanisms 

of action, so it might be difficult to assess 

therapeutic activity within the first several 

months of therapy, even with highly reliable 

measurement techniques. This difficulty in 

turn may complicate early (Phase I and II) 

trials, in which too few patients may be 

treated for a sufficient period to allow an 

accurate assessment of effects on 

progression-free and overall survival, the 

most accurate and important measures of 

biological activity for a cytostatic agent. 

For this and other reasons outlined below, it 

would be ideal if, in early-phase studies, 

novel endpoints could be used as measures 

of biological activity of the tested agent. 

Such endpoints optimally would be related 

to the mechanisms of action of the agent or 

to modulation of the putative target (e.g., 

radiographic demonstration of diminished 

blood flow after administration of an 

antiangiogenic agent). Ideally, such 

endpoints will have correlates to preclinical 

screens (e.g., the same endpoint used to 

screen and select a biological agent for 

clinical testing can be demonstrated to be 

modulated in the treated patient). Such 

endpoints could include (but are not limited 

to) in vitro assays with patient material 

(blood, urine, cerebrospinal fluid, tumor 

tissue) and imaging methodologies such as 

magnetic resonance spectroscopy or positron 

emission tomography with appropriate 

probes. Early clinical trials could be 

designed to allow for agents that achieve a 

specific threshold effect in the 

predetermined endpoint evaluation to move 

forward into further clinical development, 

ultimately leading to a definitive Phase III 

trial. 

The development of large, historical, clinical 

trials is important in order to evaluate the 

use of endpoints such as time to tumor 

progression and survival in early-phase 

trials. Such evaluations must be based on 

meaningful historical data used as controls 

against which activity and efficacy of the 

agent can be preliminarily inferred. Clinical 

endpoints for evaluating new agents must 

include quality of life measures in all Phase 

III and novel Phase II trials. The importance 

of quality of life endpoints is readily 

apparent in pediatric tumors but are also 

relevant for malignant gliomas in adults. 

The development of such endpoints and 

objective response criteria will not only aid 

in the development of novel agents but also 

allow for the accrual of knowledge about 

current therapies. Furthermore, they will 

allow earlier identification of response in 

individual patients. Determining which 

patients are helped by current therapies and 

why will aid more rational and focused 

development of new therapeutics. 

72 Report of the Brain Tumor Progress Review Group 
Novel clinical trial designs should be based 

on the demonstration that a new agent is 

able to reach and affect its intended target. 

The rarity of most CNS tumor types and the 

lack of meaningful short-term endpoints 

correlated with survival lead to difficulties 

in designing timely and effective brain 

tumor clinical trials. In order to focus more 

quickly on the highest-priority agents, 

especially for less common or slowly 

growing brain tumors, it would be helpful to 

be able to select them for further study based 

on demonstration of their ability to actually 

reach and alter their putative molecular 

targets in patients. 

An additional issue relates to the delays 

often encountered in developing 

combinations of new agents. Rational 

combinations may be expected to be no less 

important for newer drug classes directed at 

defined molecular targets than they are for 

conventional cytotoxic chemotherapies. 

However, the current regulatory system 

requires that drugs can be licensed only if 

they are sufficiently useful individually, 

even when combinations may reasonably be 

expected to be considerably more 

efficacious. To substantially speed the 

development cycle for effective 

combinations would require a systematic 

plan for combination testing that begins at 

the preclinical and Phase I and II levels of 

the process, and when carried out with 

appropriate rigor, acceptance of such a 

strategy by the Food and Drug 

Administration. 

The two adult and one pediatric brain tumor 

consortia offer excellent means to expedite 

testing of new agents, including in novel 

trial designs and in combinations. Further 

interactions with industry should be 

encouraged to provide pharmaceutical and 

biotechnology companies with access to 

tools (e.g., patient data, markers, validated 

endpoints) for evaluating potential new 

drugs. Study designs for new 

pharmacological agents should encourage 

pharmacokinetic and scientific endpoints, 

including collection of tumor and, where 

appropriate, adjacent normal neural tissue 

for pharmacological and genetic studies after 

drug delivery. Involvement of neurosurgeons 

and basic scientists in the design and 

analysis of clinical trial may facilitate this 

objective. 

Little Understanding of Drug-Radiation 

Interactions in Normal CNS Tissue 

An important challenge remains the 

development of interventions that might 

enhance radiosensitivity while diminishing 

neurotoxicity. Spatially defined radiation 

interactions with pharmacological and 

biological agents represent an exciting area 

for potential enhancement of the therapeutic 

ratio in brain tumor treatment. Further 

understanding of the interactions of 

chemotherapeutic agents and irradiation in 

normal CNS tissues should be sought. 

New avenues to exploit radiation effects 

require intensive laboratory development 

prior to expedited clinical trials in malignant 

gliomas. Such approaches include the 

delivery of tumorsensitizing or -

neuroprotective molecules via gene therapy 

coupled with focal radiation delivery. 

Exploration of radiation-induced promoters 

represents an additional focal biological 

effect that may be exploited in this tumor 

system. (See also the report of the Radiation 

Biology breakout session.) 

Treatment 73 
RESEARCH PRIORITIES 

Priority 1: 

Facilitate novel therapeutic development 

and increase knowledge about the 

mechanisms of current therapies. 

• Enhance preclinical screening: 

— Recognize that currently 

existing brain tumor animal 

models are unreliable 

predictors of clinical drug 

activity. 

— Develop a paradigm to move 

rationally developed new 

agents toward clinical trials 

primarily based on their 

ability to inhibit signaling 

pathways that are known to 

be important in the 

proliferation and/or survival 

of gliomas or other CNS 

tumors. Such a paradigm will 

require validation by 

experience, however, and 

perhaps could never displace 

entirely older designs, 

because our understanding of 

pathways and molecular 

targets is far from complete 

and will always be changing. 

Some agents will eventually 

be found to modulate 

pathways or inhibit targets in 

ways other than those 

originally assumed and 

intended. 

— Support the development of 

new animal models that more 

faithfully model human 

tumors as validated both by 

molecular characterization 

and through their 

pharmacological interactions 

and response to new and 

known cytotoxic agents. 

• Provide added resources to facilitate 

moving new therapeutic agents 

developed in the academic setting from 

laboratory compounds to clinical-grade 

drugs for therapeutic trials. 

• Increase patient accrual into clinical 

trials. 

— Increase patient awareness of 

clinical trials and the benefits 

of participation through 

advocacy groups. 

— Support a systematic effort to 

determine barriers to adult 

enrollment in brain tumor 

clinical trials, the results of 

which effort should be 

incorporated into educational 

and informational efforts to 

increase enrollment. 

— Facilitate the availability of 

innovative studies for less 

common CNS tumors or 

inclusion in ongoing trials of 

promising new therapies for 

more common CNS tumors 

in which patients can be 

analyzed as distinct 

subgroups. 

• Identify meaningful biological 

endpoints for the evaluation of new 

therapeutic approaches. 

— Develop and validate 

molecular and genetic 

endpoints (surrogate 

markers). 

— Develop and validate imaging 

endpoint parameters (e.g., 

quantitative magnetic 

resonance imaging and 

magnetic resonance 

spectroscopy). 

• Optimize study designs. 

— Identify genetic and 

epigenetic markers that more 

accurately group patients 

74 Report of the Brain Tumor Progress Review Group 
with biologically 

homogeneous tumors. 

— Formulate study designs by 

using specific biological 

endpoints that are relevant to 

the known mechanism of 

action of the agent(s) being 

tested. 

— Encourage study designs that 

incorporate tissue acquisition 

before and during treatment 

for assessment of drug 

delivery and measurement of 

biological endpoints. 

— Consider distinct designs 

appropriate to cytostatic and 

cytotoxic agents. 

— Encourage incorporation of 

functional and quality-of-life 

measures in adult and 

pediatric brain tumor studies. 

— Identify common data 

elements to facilitate the 

evaluation of new therapies 

across institutions and 

cooperative groups. 

— Establish a national data 

repository for clinical and 

genetic information to be 

available to investigators. 

Priority 2: 

Stimulate research on improving the 

therapeutic index of new agents 

specifically relevant to the CNS. 

• Develop improved methodologies for 

drug delivery (e.g., blood-brain barrier 

disruption, convection) for both 

primary intraparenchymal tumors and 

leptomeningeal tumors. 

• Develop new methodologies for 

assessing neuropharmacokinetics. 

• Develop tools for assessing toxic 

effects of drugs on the CNS 

(neurotoxicology). 

• Support enhanced research into 

potential means of neuroprotection. 

• Support research to improve the design 

and delivery of conditionally 

replicating oncolytic viral vectors and 

other gene therapy vectors used either 

alone or in conjunction with 

chemotherapy and/or radiotherapy. 

Priority 3: 

Enhance research to improve the 

therapeutic ratio for radiation therapy 

for CNS tumors. 

• Study means of enhancing 

radiosensitivity for malignant gliomas 

and other CNS tumors. 

— Develop gene transfer 

technologies providing 

radiosensitization or 

radioprotection. 

— Explore the role of radiationinducible promoters as a 

means of enhancing temporal 

and spatially specific gene 

expression. 

• Study outcomes in children treated 

with limited volume, high-technology 

radiation therapy, often at less than 

“conventional” dose levels. 

RESOURCES NEEDED 

• Resources to establish an Internetbased clinical/research database 

• Incentives to encourage industry 

interactions with academic 

investigators to identify new endpoints 

and surrogate markers important to 

testing new CNS agents 

• Increased access by academic scientists 

to centrally funded GMP capabilities in 

developing new CNS agents 

• Funding for the development and 

validation of new animal models 

Treatment 75 
specific for testing new agents in CNS 

tumors 

• Increased funding for statistical support 

in developing novel study designs 

• Funding for prospective assessment of 

imaging endpoints of therapeutic 

response based on collaborations 

between clinical investigators in 

neurooncology and neuroimaging 

• Development of central core facilities 

for in vivo animal evaluation of new 

therapeutic approaches, including 

pharmacological imaging and 

biological endpoints for 

pharmacological and biological agents, 

neurosurgery, and radiation therapy 

• Support for studies of genetically 

related alterations in radiation 

sensitivity and toxicity 

• Support for development of radiationinducible promoters to enhance 

temporal and spatial specificity of gene 

expression 

• Support for an infrastructure of 

coordinated (central or linked) tumor 

banks that would be available on a 

competitive basis to researchers in 

academia or industry in order to 

expedite development of new 

therapies. These banks would need to 

contain specimens collected and 

maintained with appropriate quality 

assurance and associated (with 

appropriate privacy safeguards) with 

validated clinical data. 

76 Report of the Brain Tumor Progress Review Group 
Extraaxial Brain Tumors

Co-chairs: Keith L. Black, M.D., Ph.D., and Stuart A. Grossman, M.D. 

Participants: 

J. Gregory Cairncross 

Webster Cavenee 

E. Antonio Chiocca 

Pam Del Maestro 

Richard A. Fishel 

Ramon Gilberto Gonzalez 

James F. Gusella 

Bruce R. Korf 

Andreas Kurtz 

Linda M. Liau 

Craig Lustig 

Robert L. Martuza 

Ed Oldfield 

Luis Parada 

David Parkinson 

David Ramsay 

Sandra Rempel 

Tom Rozman 

John H. Sampson 

Arthur W. Toga 

Mark Yarborough 

Han Ying 

Richard Youle 

STATEMENT OF THE PROBLEM 

A wide variety of extraaxial tumors arise in 

the spinal and cranial nerves and sometimes 

affect the brain by compression. Extraaxial 

tumors are uniquely interesting for brain 

tumor research for a number of reasons: 

• Extraaxial tumors tend to be more 

homogeneous than parenchymal brain 

neoplasms such as gliomas. 

• The location of extraaxial tumors 

extrinsic to the brain encourages novel 

approaches to targeted therapy and 

facilitates acquisition of tissue for 

research. 

• The early genetic changes underlying 

some extraaxial tumors are well 

characterized, including in hereditary 

syndromes, such as neurofibromatosis 

2, that predispose to these lesions. 

Extraaxial tumors that affect the brain and 

spinal cord include meningiomas, 

schwannomas, neurofibromas, and pituitary 

tumors, as well as mesenchymal tumors of 

the skull, spine, and dura mater. Although 

all of these entities may present problems in 

clinical management, two lesions, 

meningiomas and schwannomas, are 

priorities for further research because they 

are common and may be difficult to manage. 

Although surgical resection is a mainstay of 

treatment for these neoplasms, some cannot 

be resected and others may recur despite 

resection. Furthermore, some of these 

tumors remain dormant and do not require 

intervention, whereas others may grow and 

become refractory to standard therapy. 

Unfortunately, current neuroimaging 

techniques do not provide substantial 

preoperative information about the predicted 

rate of tumor growth or the likelihood of 

tumor recurrence, and current 

histopathological classification and grading 

are not adequately predictive in many cases. 

Longitudinal studies of tumor growth are 

hampered by the sometimes long intervals 

between presentation and recurrence, and 

many standard registries do not capture 

information on these lesions. Finally, 

ancillary therapies are primarily restricted to 

radiation therapy, and few other options are 

available. 

CHALLENGES AND QUESTIONS 

• To predict which meningiomas and 

schwannomas will remain dormant and 

will not require surgical 

intervention—Such information will 

direct surgery toward those patients 

who are most likely to benefit from it 

and will spare potential complications 

for other patients. 

Extraaxial Brain Tumors 77 
• To predict which meningiomas and 

schwannomas will have a greater 

likelihood of recurrence after surgical 

resection—Such information would 

allow follow-up strategies and 

therapies to be directed toward those 

patients in need while sparing 

unnecessary therapy and potential 

complications for those patients whose 

tumors will not recur. 

• To develop novel therapies for 

meningiomas and schwannomas that 

are not amenable to surgery or that 

recur after surgery—Current 

approaches are primarily restricted to 

radiation therapy, which also has 

potential neurotoxicity in extraaxial 

lesions. 

• To identify clinical and neuroimaging 

endpoints for the evaluation of 

meningioma and schwannoma growth 

and of therapeutic efficacy—Current 

endpoints, such as tumor growth, time 

to recurrence, and survival, are 

problematic given the slow growth 

characteristics of many of these 

tumors. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Understand the natural history of 

meningiomas and schwannomas, as well 

as their response to therapies. 

• Neuroimaging strategies should be 

developed that will allow prognostic 

information, anatomical or molecular, 

to be derived before surgical 

intervention. 

• Tissue-based approaches should focus 

on refined diagnoses based on 

molecular profiling. 

• Population-based studies must be 

enabled to allow follow-up of large 

numbers of patients over long periods 

and of unique populations of patients, 

such as those with neurofibromatosis 2. 

Priority 2: 

Develop outcome measurements for 

evaluating the efficacy of therapies for 

extraaxial tumors and the effects of tumor 

and therapy on quality of life. 

Priority 3: 

Develop novel therapies for extraaxial 

tumors on the basis of on their unique 

biological qualities. 

• Molecular biological research should 

elucidate the pathways responsible for 

meningioma and schwannoma 

tumorigenesis. Initial avenues for 

research would include study of 

pathways regulated by merlin (the 

protein encoded by the 

neurofibromatosis 2 gene). Such 

information could contribute to 

biologically rational approaches to 

therapy. 

• Targeted therapies should be 

investigated on the basis of the 

localized and physically separate 

nature of these tumors, as well as on 

their biological characteristics. A wide 

variety of therapeutic approaches could 

be of interest, from small-molecule 

inhibitors to antiangiogenesis to 

immunological to gene therapy. 

RESOURCES NEEDED 

• Integrated registries, tissue banks, and 

databases for meningiomas and 

schwannomas, including 

neurofibromatosis 2 

• Funding mechanisms to support longterm (e.g., >10-year) longitudinal 

studies of tumor growth rates and the 

natural history of tumors in specific 

patient populations (such as those with 

neurofibromatosis 2). Current 

78 Report of the Brain Tumor Progress Review Group 
Department of Defense grants address 

only vestibular schwannoma growth in 

patients with neurofibromatosis 2. 

Extraaxial Brain Tumors 79
Intraaxial Tumors

Co-Chairs: Faith Davis, Ph.D., and Lisa DeAngelis, M.D. 

Participants: 

Michael Berens 

Mitchel Berger 

Rebecca Betensky 

Pim Brouwers 

Peter Burger 

J. Gregory Cairncross 

Webster Cavenee 

R. Edward Coleman 

Ronald A. DePinho 

Howard A. Fine 

Candece Gladson 

Joseph C. Gloriosa 

Peter Ho 

Fred Hochberg 

Susan Hockfield 

Eric C. Holland 

William G. Kaelin Jr. 

Kathleen Lamborn 

John Mazziotta 

Minesh Mehta 

Ravi Menon 

Christina A. Meyers 

Maiken Needergaard 

Donna Neuberg 

Edward A. Neuwelt 

Lawrence Pizzi 

Jasti S. Rao 

Greg Riggins 

Elizabeth Stevenson 

Michael Walker 

Albert Wong 

Roy S. Wu 

W. K. Alfred Yung 

STATEMENT OF THE PROBLEM 

Intraaxial tumors comprise a complex 

mixture of low- and high-grade lesions 

occurring in both children and adults. This 

report restricts its discussion to adult tumors 

other than malignant gliomas, specifically 

low-grade gliomas, lymphomas, and germ 

cell tumors. 

Low-grade gliomas can be divided into two 

general categories: infiltrating and localized. 

Infiltrating tumors include, but are not 

limited to, fibrillary astrocytomas, 

oligodendrogliomas, and ependymomas. 

Non-infiltrating tumors include pleomorphic 

xanthoastrocytomas, pilocytic astrocytomas, 

and dysembryoplastic neuroepithelial 

tumors. Despite their rarity, primary central 

nervous system (CNS) lymphomas and germ 

cell tumors are also important because some 

patients are cured of their tumors. However, 

not all patients are cured, and some of those 

who are suffer long-term neurotoxicity. 

CHALLENGES 

Although numerous in the aggregate, each 

tumor type is uncommon. Patient numbers 

are small, and no single institution acquires 

adequate numbers to answer important 

questions. 

Tissue for study is limited. Often only a 

needle biopsy is available, and sometimes, 

as in infiltrating low-grade gliomas, no 

tissue is available. This creates particular 

challenges for molecular studies. Imaging 

techniques may provide an alternative 

approach for the investigators to noninvasively “examine” the entire tumor. 

Development of biological and molecular 

imaging technologies is essential for further 

understanding of these less common 

intraaxial neoplasms. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Low-Grade Gliomas 

Priority 1: 

Better understand the natural history of 

low-grade gliomas with an emphasis on 

mechanisms of progression, infiltration or 

lack of it in non-invasive diagnosis. 

80 Report of the Brain Tumor Progress Review Group 
Imaging strategies should be developed 

to: 

• Identify the extent of infiltrating tumor 

• Predict progression 

• Identify heterogeneity prior to surgery 

or biopsy 

Priority 2: 

Develop techniques to molecularly 

characterize tumors on small biopsy 

samples. 

• Particular emphasis should be placed 

on the molecular signature of tumors 

that infiltrate and progress to higher 

grade. 

• Conduct population-based studies to 

allow assessment of etiology and new 

treatment strategies, including their 

toxicity and patients’ quality of life. 

Primary CNS Lymphoma and Germ Cell 

Tumors 

Priority 3: 

Understand the natural history of 

primary CNS lymphomas. 

• Epidemiologic studies are needed to 

identify environmental factors other 

than immune suppression that appear 

to be leading to an increased incidence 

of lymphomas. 

• Molecular characterization of CNS 

lymphomas is required to determine 

how they differ from systemic 

lymphoma, identify the cell of origin, 

and predict prognosis. Molecular 

characterization of germinomas is 

needed for prognostic prediction. 

Priority 4: 

Develop more effective therapies. 

• Conduct long-term studies on dose 

intensity for the treatment of 

lymphomas and determination of 

optimum volume for radiation therapy 

for germinomas. 

• Determine the relationship between 

molecular characterization of the tumor 

and response to therapy is required. 

• Long-term studies of neurotoxicity 

require development of quantitative 

quality of life and neurocognitive 

instruments, development of treatment 

strategies to improve cognition, and 

further study on how the tumor itself 

may affect brain function. 

RESOURCES NEEDED 

• Funding for the establishment of cell 

lines of each of these tumor types is 

necessary to learn more about the 

biology of these tumors. 

• A central repository for tissue banking 

for genetic analysis of tumors should 

be established to draw samples from all 

over the country. 

• A central registry or database should be 

established to accumulate clinical 

information on diagnosis, response to 

treatment, neurotoxicity, and long-term 

follow-up of patients with these 

tumors. Support should be provided for 

long-term longitudinal studies. 

81
Metastasis

Co-chairs: Bertrand C. Liang, M.D., and Roy A. Patchell, M.D. 

Participants: 

Darell D. Bigner 

Peter M. Black 

Ronald G. Blasberg 

Carol Kruchko 

Rolando Del Maestro 

Glenn Dranoff 

Lester Drewes 

Brian Fuller 

Peter Inskip 

Lois Lampson 

Jay Loeffler 

William M. Pardridge 

Lynn A. Ries 

Harald Sontheimer 

Philip J. Tofilon 

Jeannine Walston 

Carol Wikstrand 

Jeanne Young 

John S. Yu 

STATEMENT OF THE PROBLEM 

Central nervous system (CNS) metastases 

are a serious and common problem in 

patients with systemic cancer. Brain 

metastases are at least 10 times more 

frequent than primary brain tumors. 

Leptomeningeal metastasis affects about 5% 

of cancer patients, and spinal cord 

compression due to metastases occurs in 

5–10% of patients with systemic 

malignancies. Despite refinements in surgery 

and radiotherapy, many patients die from 

CNS metastases, and long-term survivors 

often suffer devastating side effects of their 

treatment. 

Despite the large number of patients 

affected, metastatic disease to the 

nervous system is an area that has been 

largely neglected by investigators. CNS 

metastases are an “orphan” area falling 

between the classic areas of tumor 

biology/medical oncology and neuroscience, 

as shown by the dearth of extramurally 

funded grants in the National Cancer 

Institute (NCI) and National Institute of 

Neurological Disorders and Stroke (NINDS) 

portfolios. As a result, understanding of the 

general cellular and molecular mechanisms 

involved in metastasis has lagged behind 

that of other advances in the basic sciences 

related to oncology and neuroscience. 

CHALLENGES 

The main problem in the area of CNS 

metastatic disease is the scarcity of data on 

the biology of the disease that can be applied 

to clinical approaches to prevention and 

treatment. Other challenges are as follows: 

• Obtaining tissue from both the primary 

tumor and the CNS metastasis in order 

to understand the fundamental biology 

of metastases to the nervous system. 

• Including patients with CNS metastasis 

in protocols for treatment of systemic 

disease. All too often, innovative 

protocols for the treatment of cancer 

specifically exclude brain and other 

CNS metastases because of the belief 

that metastases in the CNS do not 

respond to treatments that affect the 

cancer elsewhere in the body. 

• Increasing the interest of the 

neuroscience and neuro-oncological 

community in the biology and 

treatment of CNS metastases. 

RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Identify genetic/cellular/molecular factors 

that allow metastatic disease to establish 

itself in the CNS. These factors include: 

82 Report of the Brain Tumor Progress Review Group 
• 

Biology of the CNS microenvironment 

• Basement membrane biology 

•Interaction of genotypic/phenotypic 

metastatic cells with the CNS 

microenvironment 

•Immune system interactions within the 

phenotype of metastatic cells into the 

nervous system 

Priority 2: 

Identify factors that may prevent metastases to the nervous system: • Develop new animal models of de 

novo metastatic disease to the CNS. 

•Evaluate potential markers in systemic 

cancers that predict CNS metastasis. 

•Develop agents to prevent CNS 

metastasis. 

Priority 3: 

Identify targets of established disease: 

•Develop new imaging techniques to 

identify CNS metastases earlier than is 

presently possible. 

•Develop appropriate clinical endpoints for clinical trials of prevention and 

therapy as well as instruments to 

measure quality of life. 

RESOURCES NEEDED 

•A tissue bank to include tissue from a 

primary tumor and tissue from its CNS 

metastases. 

•New animal models for brain and 

leptomeningeal metastasis. 

•A Progress Review Group that deals exclusively with metastasis. 

•Specific NIH initiatives to study 

metastatic disease to the nervous 

system. 

Metastasis 83 
Pediatric Brain Tumors

Co-Chairs: Roger Packer, M.D., and Ian Pollack, M.D. 

Participants: 

Francis Ali-Osman 

David Ashley 

Jaclyn A. Biegel 

James Boyette 

Greta Bunin 

Tom Curran 

Henry Friedman 

James Goldman 

Daphne A. HaasKogen 

Alison Hannah 

Mark A. Israel 

C. David James 

David Kaplan 

Kenneth A. Krohn 

Larry Kun 

Frederick F. Lang 

Marla B. Luskin 

Lorraine Marin 

Robert H. Miller 

Sherie Morrison 

Raymond Mulhern 

Sarah Nelson 

Judith J. Ochs 

Scott Pomeroy 

Sam D. Rabkin 

Richard Ransohoff 

Lucy B. Rorke 

Bruce Rosen 

David H. Rowitch 

James Rutka 

Gail Segal 

Dennis C. Shrieve 

Malcolm Smith 

Evan Snyder 

Diane Traynor 

Richard Vallee 

Jeanne Young 

Susan L. Weiner 

STATEMENT OF THE PROBLEM 

Childhood brain tumors are the second most 

frequent malignancy of childhood and the 

most common form of solid tumor. Tumors 

of the central nervous system (CNS) 

comprise 22% of all malignancies occurring 

among children up to 14 years of age and 

10% of tumors occurring among 15–19-

year-olds. Although rapid progress has been 

made in the treatment of some forms of 

childhood cancer, such as acute lymphatic 

leukemia, the outcome for children with 

primary CNS tumors has remained poor and 

for most tumors has not changed over the 

past decade. Brain tumors are now the 

leading cause of death from childhood 

cancer, accounting for 24% of cancer-related 

deaths in 1997 among persons up to 19 years 

of age. In addition, due to either the effects 

of the tumor or the treatment required to 

control it, survivors of childhood brain 

tumors often have severe neurologic, 

neurocognitive, and psychosocial sequelae. 

Tumors in childhood differ significantly 

from adult lesions in their sites of origin, 

histological features, clinical presentations, 

and proclivity to disseminate throughout the 

nervous system early in the course of illness. 

Whereas 90% of adult tumors arise in the 

cerebral cortex, 50% of childhood brain 

tumors originate infratentorially, in the 

cerebellum, brain stem, or fourth ventricular 

region. A large proportion of brain tumors in 

adults are the result of metastatic lesions 

from nonprimary brain sites, and the primary 

tumors are for the most part glial tumors and 

meningiomas. In contrast, childhood brain 

tumors mainly represent primary CNS 

lesions and, although gliomas make up the 

majority of childhood neoplasms, other 

tumor type,s such as medulloblastomas, 

primitive neuroectodermal tumors, 

pineoblastomas, atypical teratoid tumors, 

and other embryonal neoplasms, contribute a 

significant proportion. 

The biological behavior and management of 

childhood tumors depends on not only the 

histological character of the tumor but also 

its location within the nervous system. For 

example, childhood low-grade cerebellar 

gliomas may be curable in over 90% of 

patients with surgery alone, whereas brain 

stem gliomas (even if “low-grade”) carry the 

dismal prognosis of death for most child 

patients within 18 months of diagnosis. The 

84 Report of the Brain Tumor Progress Review Group 
aspects of tumor dissemination are 

extremely important for childhood brain 

tumors. Control of local disease remains 

problematic for many forms of childhood 

brain tumors; however, specific types of 

tumors, especially embryonal tumors, have a 

high proclivity for early dissemination 

within the nervous system and treatment 

approaches must take into account this 

tendency for early tumor spread. The 

neurobiological underpinnings of these 

differences are largely unknown: the 

importance of the relationship between 

tumor type and location is poorly studied; 

the reasons why tumors primarily arise at 

certain ages and have proclivity to specific 

areas of brain are unclear; and the ways to 

utilize these differences to alter management 

and improve outcome require further 

investigation. 

The histological heterogeneity of childhood 

brain tumors makes it necessary to develop 

separate lines of investigation into the 

molecular mechanisms of each type of 

tumor, the effect of the surrounding milieu 

on the tumor, and the development of 

effective treatment approaches. A variety of 

different classification systems have been 

utilized for childhood brain tumors, and 

controversy still exists concerning the most 

appropriate nomenclature for some tumors. 

The classification systems in use are still 

based on relatively subjective criteria, 

making comparison across different studies 

difficult. Although some subtypes of 

childhood brain tumors are relatively rare, 

such as primitive neuroectodermal tumors 

(excluding medulloblastoma), atypical 

teratoid tumors, medulloepitheliomas, 

dysembryoplastic neuroepithelial tumors, 

desmoplastic infantile gangliogliomas, and 

superficial cerebral astrocytomas of infancy, 

together they constitute a significant 

percentage of childhood brain tumors and a 

major cause of morbidity and mortality. 

Studies focusing on the more frequent adult 

and pediatric CNS tumors often do not 

include such rare tumors, which results in 

missed opportunities to understand these 

tumors’ biology and create more effective 

treatment regimens. 

Even within the tumor types commonly 

found in both children and adults, studies 

focusing on tumors occurring in adults may 

not result in new insights for pediatric 

tumors. The molecular aspects of glial 

neoplasia in children, for example, appear to 

differ substantially from those in adults. 

Most childhood low-grade gliomas are 

pilocytic astrocytomas, whereas this tumor 

type is relatively infrequent in adults. 

Pilocytic astrocytomas have a different 

biology than fibrillary or other grade 2 

lesions. For example, one major difference 

is that pilocytic astrocytomas rarely mutate 

into higher-grade lesions, whereas fibrillary 

astrocytomas often do so. Furthermore, even 

fibrillary low-grade gliomas in childhood 

rarely mutate into higher-grade tumors in the 

childhood years, despite this common 

occurrence in adults. For progress to be 

made in this subset of tumors, research must 

be focused directly on pediatric low-grade 

gliomas. 

The differences between the neurobiological 

features of glial neoplasia in children and 

those of the disease in adults are not limited 

to low-grade tumors. Approximately 40% of 

grade IV gliomas in adults exhibit 

amplification of epidermal growth factor 

receptor, whereas this change is less 

commonly detected in childhood 

glioblastomas. In addition, P53 mutations, 

which are observed in 50% of grade III and 

grade IV gliomas in adults, are rarely seen in 

high-grade gliomas in children. These 

differences may at least partly account for 

the somewhat better prognosis for childhood 

high-grade gliomas; a subset of children 

with high-grade glial tumors, including 

glioblastoma multiforme (as high as 20% in 

some studies), survive after treatment. In 

addition, evidence from randomized 

Pediatric Brain Tumors 85 
prospective studies shows that long-term 

survival for childhood glioblastoma 

multiforme is improved by the addition of 

chemotherapy to radiotherapy; such data are 

lacking in adults. 

A focused effort to define relevant molecular 

markers for prognosis in childhood glial 

tumors may facilitate improved diagnostic 

and therapeutic stratification of patients and 

more appropriate treatment. Treatment 

strategies may also need to differ for 

childhood and adult high-grade gliomas. 

Also needed are innovative classification 

systems that integrate molecular, 

neurobiological, and neuroimaging aspects 

with histological diagnosis to develop more 

clinically relevant nomenclatures for these 

tumors; this will guide epidemiological 

research, biological studies, and treatment 

approaches. 

The molecular pathways involved in the 

development of primitive neuroectodermal 

tumors are just being unraveled. Research 

focused on the glial tumors that predominate 

in adults may not lead to a better 

understanding of these primitive embryonal 

tumors. Although such tumors are not 

unique to childhood, they are substantially 

more common in children than in adults. 

There has been significant controversy over 

the most appropriate classification of 

childhood primitive neuroectodermal 

tumors, primarily whether all such tumors 

should be grouped into one category or 

better subdivided based purely on tumor 

location. Recent studies have suggested, 

although not proven, that although these 

tumors share histological similarities, 

molecular features of the lesions occurring 

outside the posterior fossa are distinct from 

those arising in the posterior fossa. In 

addition, studies have recently shown that 

other molecular features, such as TrkC 

expression, correlate with outcome in 

medulloblastoma and may lead to better 

stratification systems. Other neurobiological 

abnormalities have been noted in these 

primitive neuroectodermal tumors, and 

research into the molecular pathways 

involved in tumor development and growth 

is needed. 

Infants and very young children with 

primary CNS tumors often harbor lesions 

that are apparently unique to the early 

childhood years. Some of these tumors, such 

as atypical teratoid tumors and 

medulloepithelioma, although rare, are a 

significant problem in the pediatric age 

range. More global investigations into brain 

tumors, especially research focusing on 

more common adult tumors, will fail to 

address these important lesions. Many of 

these embryonal tumors are apparently true 

congenital tumors, and studies of the 

mechanism of their development may also 

lead to important insights into general brain 

development. Similarly, studies of brain 

development may lead to insights into the 

neurobiological aspects of these and other 

embryonal tumors. 

Also related to age are the effects of therapy 

on the developing nervous system. As stated 

previously, some childhood brain tumors are 

true congenital lesions, whereas others, such 

as medulloblastoma and ependymoma, peak 

in incidence before age 5 years. Given the 

proclivity of primitive tumors to disseminate 

within the nervous system early in the course 

of disease, treatment approaches must focus 

on controlling not only local disease but also 

disease in all sites of the nervous system. 

This often requires treatment to be aimed at 

the entire nervous system in the young child 

and heightens the likelihood of treatmentrelated brain injury. 

The long-term effects of the tumor and its 

treatment on outcome are extremely 

important issues in both children and adults 

with brain tumors, but because of the abovementioned reasons, they take on even more 

significance in childhood. It has been well 

86 Report of the Brain Tumor Progress Review Group 
documented that young children with brain 

tumors, independent of the form of treatment 

they receive, have significant neurological 

and cognitive sequelae. Furthermore, for 

older children and adolescents, treatment 

may result in permanent long-term sequelae, 

especially neurocognitive difficulties. Other 

common sequelae include endocrinological 

dysfunction, focal neurological deficits, and 

psychosocial sequelae. 

In a recent retrospective questionnaire 

review of 1,845 children with brain tumors 

who survived for at least 5 years, it was 

noted that seizures, convulsions, or 

blackouts occurred in 28% of survivors; 

headaches, including migraines, were a 

problem in 37% of patients; and motor 

disabilities, such as balance problems, 

weakness of the arms of legs, or tremors, 

were noted in over 50% of children. A 

sizeable minority of patients had blindness 

in one or both eyes, double vision, hearing 

loss, or persistent tinnitus. Over 50% of 

those surviving for 5 years from the date of 

diagnosis of their childhood brain tumors 

required special education or learningdisabled classroom settings, including 70% 

of those less than 3 years of age and 62% of 

those between 3 and 9 years of age. The 

incidence of secondary brain tumors in longterm survivors of childhood brain tumors is 

rising, and second malignancies are almost 

always fatal for this patient population. 

These sobering numbers highlight the 

problems faced by survivors of childhood 

brain tumors and the need for further 

research into means to reduce long-term 

sequelae and remediate such problems when 

they arise. 

CHALLENGES AND QUESTIONS 

On the largest scale, the overriding 

challenge for research into pediatric brain 

tumors is to improve outcome for children 

with a host of different types of brain 

tumors. The predominant barriers are the 

relative infrequency of any individual tumor 

type, the presence of embryonal/primitive 

tumors that often disseminate to the 

leptomeninges, and the lack of interest in, 

focus on, and funding for research on these 

primitive tumors. Specific challenges 

associated with improving outcomes for 

children with pediatric brain tumors and 

barriers to meeting these challenges are 

grouped below into four categories: Tumor 

Biology, Epidemiology, Treatment, and 

Long-Term Sequelae. 

TUMOR BIOLOGY 

Challenges 

• Improved understanding of the genetic 

and environmental factors involved in 

the development of childhood CNS 

tumors 

• Increased understanding of the cellular 

origin of different types of pediatric 

brain tumors 

• Greater insight into the relationship 

between normal brain development and 

the neurogenetic/biologic 

underpinnings of childhood nervous 

system tumors 

• Determination of factors responsible 

for the proclivity of some childhood 

brain tumors to disseminate within the 

nervous system early in the course of 

illness 

• Clarification of the relationship 

between age, development, and 

outcome of childhood brain tumors 

• Enhanced understanding of the 

biologic differences between childhood 

and adult gliomas and the development 

of treatment approaches that take 

advantage of such differences 

• Better understanding of the 

neurobiology of childhood primitive 

neuroectodermal tumors (including 

medulloblastoma) and other less 

common embryonal tumors 

Pediatric Brain Tumors 87 
• Development of better animal models 

that mimic human pediatric brain 

tumors, including those primarily 

occurring in children, such as PNETs 

and other rarer pediatric tumors (e.g., 

atypical teratoid tumors) 

• Definition of relevant molecular 

markers for the prognosis of the 

diverse forms of childhood brain 

tumors 

Barriers 

• Insufficient appreciation of the 

important distinction between research 

required for childhood brain tumors 

and research required for adult tumors 

• Lack of emphasis placed on the 

defining biologic differences between 

histologically identical tumors 

occurring in children and adults, 

especially the low- and high-grade 

gliomas 

• Paucity of investigations focused on 

the molecular, genetic, and biologic 

aspects of embryonal childhood brain 

tumors, including primitive 

neuroectodermal tumors 

• Lack of understanding of the 

relationship between normal brain 

development and aberrations of such 

development in the etiology of 

childhood brain tumors 

• Lack of understanding of the 

uniqueness of the rarer childhood brain 

tumors; their overall importance, in 

total; and the need to study these types 

of neoplasms individually 

• Lack of usable surrogate markers to 

determine the prognosis of childhood 

brain tumors and to evaluate the 

potential efficacy of agents used to 

treat such tumors 

EPIDEMIOLOGY 

Challenges 

• Creation of a biologically-based 

classification of childhood brain 

tumors that integrates molecular 

aspects, neurobiological parameters 

and other neurodiagnostic findings 

• Determination of the incidence of 

individual types of childhood brain 

tumors, including low grade 

neoplasms, congenital tumors, and 

embryonal neoplasms 

Barriers 

• Variability in the classification of rare 

childhood brain tumors, especially 

congenital and embryonal lesions 

• Lack of methods to study individual 

tumor types that occur less commonly 

• New coding of low-grade gliomas as 

“benign” tumors, which could increase 

the likelihood that children with these 

diagnoses will not be included in 

cancer registries 

• Lack of funding for epidemiological 

research, especially for the less 

common, but critically important, 

childhood brain tumor subtypes 

TREATMENT 

Challenges 

• Development of more effective 

treatments for childhood low- and 

high-grade gliomas 

• Development of more effective and 

safer treatment approaches for 

childhood embryonal and primitive 

tumors 

• Development of immunotherapeutic 

approaches aimed at improving control 

of localized and disseminated pediatric 

brain tumor disease 

• Development of new, safer approaches 

to control CNS disseminated disease 

88 Report of the Brain Tumor Progress Review Group 
• Development of innovative 

biologically-based treatments for 

childhood brain tumors 

Barriers 

• Reluctance of industry to focus on 

developing drugs for pediatric brain 

tumors because of the relative rarity of 

childhood brain tumors 

• Difficulty in performing clinical trials 

for specific brain tumor subtypes 

because of the relative infrequency of 

specific types of childhood brain 

tumors 

• Insufficient development of novel 

therapeutics designed for childhood 

brain tumors such as primitive 

neuroectodermal tumors 

• Hesitancy to apply new therapies early 

in their development, especially 

biologically-based treatments, to 

childhood brain tumors 

• Paucity of research into the impact of 

new neurobiological treatments, such 

as anti-growth factor agents and antiangiogenesis agents, on the developing 

nervous system 

• Limited scope of research focused on 

the immunocompetence of children 

with brain tumors and the potential 

utility of different immunotherapeutic 

approaches for children with brain 

tumors 

LONG-TERM SEQUELAE 

Challenges 

• Detection of long-term neurologic, 

cognitive, endocrinologic, systemic 

and psychosocial sequelae of childhood 

brain tumors and their treatments, and 

determination of the incidence of these 

sequelae 

• Investigation into factors that are 

involved in the development of 

neurotoxicity and host 

neurobiological/genetic characteristics 

that underlie the variable severity of 

neurologic compromise in an 

individual child 

• Development of new strategies to 

prevent, ameliorate and remediate 

neurocognitive and psychosocial 

sequelae of childhood brain tumors and 

their treatment 

• Evaluation of the impact of innovative 

biologically-based therapies on the 

developing nervous system 

• Research into factors involved in the 

development of secondary tumors in 

long-term survivors of pediatric brain 

tumors and more effective means to 

treat such secondary malignancies. 

• Research into the effects of the 

diagnosis of a brain tumor on the 

family unit, especially parental 

relationships and the impact on other 

children in the family 

Barriers 

• Lack of appreciation of the severe 

long-term sequelae suffered by 

children who have brain tumors, either 

due to their tumor or its treatment 

• Lack of emphasis on the psychosocial 

sequelae of these tumors on the child 

and the family 

• Lack of information concerning the 

development and treatment of second 

malignancies in childhood brain tumor 

survivors 

• Lack of neuro-investigative techniques 

which take into account the developing 

nervous system and the differences 

required in evaluation between adults 

and children 

Pediatric Brain Tumors 89 
RESEARCH AND SCIENTIFIC 

PRIORITIES 

Priority 1: 

Understand the signaling systems 

involved in mitogenesis, survival, and cell 

death for pediatric tumors. 

• Understand how these signaling 

systems relate to those in 

developmental neurobiology 

• Use this understanding to identify new 

targets for pediatric brain tumor 

therapy. 

Priority 2: 

Fully characterize the phenotypic and 

genetic alterations that are unique to 

benign and malignant pediatric brain 

tumors. 

• Develop novel in vitro and animal 

models that faithfully recapitulate the 

biology of these tumors. 

• Use these models for the identification 

and prioritization of targeted 

therapeutic strategies for pediatric 

brain tumors. 

Priority 3: 

Investigate in detail the impact of the 

tumor and its treatment on long-term 

neurological, cognitive, and psychological 

functional outcome, and develop new 

means to prevent, ameliorate, and 

remediate such dysfunction. 

Priority 4: 

Conduct pediatric clinical trials of novel 

therapeutic agents at an appropriately 

early stage in their development; include 

in these trials comprehensive and 

noninvasive assessments (including 

innovative imaging and biological studies) 

of the short- and long-term effects of such 

agents on the child and on the developing 

nervous system. 

RESOURCES NEEDED 

• Tumor banking of pediatric brain 

tumor tissues 

• DNA microarrays applicable to 

pediatric brain tumors and nervous 

system development 

• Tissue arrays for pediatric CNS tumors 

• Development of in vitro model systems 

for pediatric brain tumors 

• Animal model systems for pediatric 

brain tumors 

• Greater availability of wellcharacterized and validated clones or 

lines of stem cells 

• Imaging techniques for identifying 

tumors in situ for animal models of 

pediatric tumors 

• Coordinated effort, on a national basis, 

of core facilities or coordinated 

individual laboratories with specific 

expertise and models (both academic 

and private industry) to facilitate the 

development of new drugs, biological 

agents, or other treatment approaches 

• Funding for neuropsychological testing 

• Validated, user-friendly, pediatric 

instrument for measuring quality of life 

• Development of neuroimaging 

techniques that correlate with 

subclinical and clinical neurotoxicity. 

90 Report of the Brain Tumor Progress Review Group 
Appendix 2: Rosters
Brain Tumor Progress Review Group

Participant Roster

David N. Louis, M.D. 

Massachusetts General Hospital

Co-Chair 

Thomas Jacobs, Ph.D. 

National Institute of Neurological

Disorders and Stroke

Executive Director

Francis Ali-Osman, D.Sc. 

M.D. Anderson Cancer Center 

Darell D. Bigner, M.D., Ph.D. 

Duke University

Keith L. Black, M.D., Ph.D. 

Cedars-Sinai Medical Center 

J. Gregory Cairncross, M.D. 

London (Ontario) Regional Cancer Center 

Webster Cavenee, Ph.D. 

Ludwig Institute for Cancer Research

Faith G. Davis, Ph.D. 

University of Illinois-Chicago 

Howard Fine, M.D. 

National Cancer Institute

James E. Goldman, M.D., Ph.D. 

Columbia University

Peter T.C. Ho, M.D., Ph.D. 

Dupont Pharmaceuticals 

Bertrand Liang, M.D. 

Amgen, Inc. 

Robert L. Martuza, M.D. 

Massachusetts General Hospital 

Jerome B. Posner, M.D. 

Memorial Sloan-Kettering Cancer Center 

Co-Chair 

Richard Kaplan, M.D. 

National Cancer Institute 

Executive Director 

John Mazziotta, M.D., Ph.D. 

University of California - Los Angeles 

Christina Meyers, Ph.D. 

M.D. Anderson Cancer Center 

Robert H. Miller, Ph.D. 

Case Western Reserve University

Donna Neuberg, Sc.D. 

Dana-Farber Cancer Institute

Cherie Nichols, M.B.A. 

National Cancer Institute

Roger Packer, M.D. 

Children’s National Medical Center 

William M. Pardridge, M.D. 

University of California - Los Angeles 

Dennis C. Shrieve, M.D., Ph.D. 

University of Arkansas for Medical Sciences 

Robert Strausberg, Ph.D. 

National Cancer Institute

Susan L. Weiner, Ph.D. 

Brain Tumor Coalition

BTPRG Roster 91 
Brain Tumor Progress Review Group Roundtable Meeting 

July 5–7, 2000 

PARTICIPANT ROSTER

Francis Ali-Osman, D.Sc. 

University of Texas M.D. Anderson Cancer 

Center 

David M. Ashley, Ph.D., F.R.A.C.P. 

Royal Children’s Hospital of Parkville 

Melbourne, Australia 

Toby Behar, Ph.D. 

National Institute of Neurological Disorders 

and Stroke 

Michael E. Berens, Ph.D. 

Barrow Neurological Institute 

Phoenix, AZ 

Mitchel Berger, M.D. 

University of California, San Francisco 

Rebecca Betensky, Ph.D. 

Harvard School of Public Health 

Jaclyn Biegel, Ph.D. 

Children’s Hospital of Philadelphia 

University of Pennsylvania School of 

Medicine 

Darell D. Bigner, M.D., Ph.D. 

Duke University Medical Center 

Keith L. Black, M.D. 

Maxine Dunitz Neurosurgical Institute 

Cedars-Sinai Medical Center 

Peter M. Black, M.D., Ph.D. 

Brigham and Women’s Hospital 

Ronald G. Blasberg, M.D. 

Memorial Sloan-Kettering Cancer Center 

James M. Boyett, Ph.D. 

St. Jude Children’s Research Hospital 

Pim Brouwers, Ph.D. 

Baylor College of Medicine 

Greta Bunin, Ph.D. 

Children’s Hospital of Philadelphia 

Peter C. Burger, M.D. 

Johns Hopkins University 

J. Gregory Cairncross, M.D. 

London (Ontario) Regional Cancer Centre 

Kevin M. Callahan, Ph.D. 

National Cancer Institute 

Webster K. Cavenee, Ph.D. 

University of California, San Diego 

Antonio E. Chiocca, M.D., Ph.D. 

Massachusetts General Hospital 

C. Norman Coleman, M.D. 

National Cancer Institute 

R. Edward Coleman, M.D. 

Duke University Medical Center 

Tom Curran, Ph.D. 

St. Jude Children’s Research Hospital 

Faith Davis, Ph.D. 

University of Illinois 

Lisa M. DeAngelis, M.D. 

Memorial Sloan-Kettering Cancer Center 

Pam Del Maestro, R.N. 

University of Ontario 

92 Report of the Brain Tumor Progress Review Group 
Rolando Del Maestro, M.D., Ph.D. 

University of Ontario 

Ronald A. DePinho, M.D. 

Dana-Farber Cancer Institute 

Glenn Dranoff, M.D. 

Dana-Farber Cancer Institute 

Lester R. Drewes, Ph.D. 

University of Minnesota, Duluth 

David Eckstein, Ph.D. 

National Institute of Neurological Disorders 

and Stroke 

Howard Fine, M.D. 

National Cancer Institute 

Richard Fishel, Ph.D. 

Thomas Jefferson University 

Henry S. Friedman, M.D. 

Duke University Medical Center 

Brian Fuller, M.D. 

National Cancer Institute 

Candece L. Gladson, M.D. 

University of Alabama at Birmingham 

Joseph C. Glorioso, Ph.D. 

University of Pittsburgh School of Medicine 

James E. Goldman, M.D., Ph.D. 

Columbia University 

Ramon Gilberto Gonzalez, M.D., Ph.D. 

Massachusetts General Hospital 

Rashmi Gopal-Srivastava, Ph.D. 

National Cancer Institute 

Stuart A. Grossman, M.D. 

Johns Hopkins University 

James F. Gusella, Ph.D. 

Massachusetts General Hospital 

Daphne A. Haas-Kogan, M.D. 

University of California, San Francisco 

Terri Hallquist, M.S. 

National Cancer Institute 

Alison L. Hannah, M.B.B.S. 

Sugen, Inc. 

Peter T.C. Ho, M.D., Ph.D. 

DuPont Pharmaceuticals Company 

Fred Hochberg, M.D. 

Massachusetts General Hospital 

Susan Hockfield, Ph.D. 

Yale University 

John M. Hoffman, M.D. 

National Cancer Institute 

Eric C. Holland, M.D., Ph.D. 

University of Texas M.D. Anderson Cancer 

Center 

Peter D. Inskip, Sc.D. 

National Cancer Institute 

Mark A. Israel, M.D. 

University of California, San Francisco 

Thomas P. Jacobs, Ph.D. 

National Institute of Neurological Disorders 

and Stroke 

C. David James, Ph.D. 

Mayo Clinic Cancer Center 

William G. Kaelin, M.D. 

Dana-Farber Cancer Institute 

Howard Hughes Medical Institute 

Harvard Medical School 

Roundtable Roster 93 
David Kaplan, Ph.D. 

Montreal Neurological Institute 

McGill University 

Richard S. Kaplan, M.D., F.A.C.P. 

National Cancer Institute 

Bruce Korf, M.D., Ph.D. 

Partners Center for Human Genetics 

Kenneth A. Krohn, Ph.D. 

University of Washington Medical Center 

Carol Kruchko 

Central Brain Tumor Registry of the United 

States 

Larry E. Kun, M.D. 

St. Jude Children’s Research Hospital 

Andreas Kurtz, Ph.D. 

Massachusetts General Hospital 

Kathleen R. Lamborn, Ph.D. 

University of California, San Francisco 

Lois A. Lampson, Ph.D. 

Brigham and Women’s Hospital 

Harvard Medical School 

Frederick F. Lang, M.D. 

University of Texas M.D. Anderson 

Cancer Center 

Anna T. Levy, M.S. 

National Cancer Institute 

Bertrand C. Liang, M.D. 

Amgen, Inc. 

Linda M. Liau, M.D., Ph.D. 

University of California, Los Angeles 

School of Medicine 

Jay S. Loeffler, M.D. 

Massachusetts General Hospital 

David N. Louis, M.D. 

Massachusetts General Hospital 

Marla B. Luskin, Ph.D. 

Emory University School of Medicine 

Craig Lustig, M.P.A. 

Children’s Brain Tumor Foundation 

Lorraine Marin, M.D. 

Preuss Foundation for Brain Tumor 

Research 

Robert L. Martuza, M.D. 

Massachusetts General Hospital 

John C. Mazziotta, M.D., Ph.D. 

University of California, Los Angeles 

Minesh P. Mehta, M.D. 

University of Wisconsin 

Madison Medical School 

Ravi S. Menon, Ph.D. 

Roberts Research Institute 

Christina A. Meyers, Ph.D. 

University of Texas M.D. Anderson Cancer 

Center 

Judy Mietz, Ph.D. 

National Cancer Institute 

Robert H. Miller, Ph.D. 

Case Western Reserve University School of 

Medicine 

Sherie Morrison, Ph.D. 

University of California, Los Angeles 

Raymond K. Mulhern, Ph.D. 

St. Jude Children’s Research Hospital 

Kate Nagy, M.A. 

National Cancer Institute 

94 Report of the Brain Tumor Progress Review Group 
Maiken Nedergaard, M.D., Ph.D. 

New York Medical College 

Sarah J. Nelson, Ph.D. 

University of California, San Francisco 

Donna Neuberg, Sc.D. 

Dana-Farber Cancer Institute 

Edward A. Neuwelt, M.D. 

Oregon Health Sciences University 

Cherie Nichols, M.B.A. 

National Cancer Institute 

Judith Ochs, M.D. 

AstraZeneca Pharmaceuticals, Inc. 

Edward H. Oldfield, M.D. 

National Institute of Neurological Disorders 

and Stroke 

Roger I. Packer, M.D. 

Children’s National Medical Center 

Luis Parada, Ph.D. 

University of TexasSouthwestern Medical 

Center at Dallas 

William M. Pardridge, M.D. 

University of California, Los Angeles 

School of Medicine 

David R. Parkinson, M.D. 

Roy A. Patchell, M.D. 

University of Kentucky 

Audrey S. Penn, M.D. 

National Institute of Neurological Disorders 

and Stroke 

Lawrence Pizzi, M.A. 

North American Brain Tumor Coalition 

Ian F. Pollack, M.D. 

Children’s Hospital of Pittsburgh 

Scott L. Pomeroy, M.D., Ph.D. 

Boston Children’s Hospital 

Jerome B. Posner, M.D. 

Memorial Sloan-Kettering Cancer Center 

Vernon G. Pursel, Ph.D. 

U.S. Department of Agriculture 

Samuel Rabkin, Ph.D. 

Massachusetts General Hospital 

David B. Ramsay, M.D. 

London Health Sciences Centre 

Richard M. Ransohoff, M.D. 

Cleveland Clinic Foundation 

Jasti S. Rao, Ph.D. 

University of Texas M.D. Anderson Cancer 

Center 

Sandra A. Rempel, Ph.D. 

Henry Ford Hospital, Detroit 

Lynn Ries, M.S. 

National Cancer Institute 

Gregory Riggins, M.D., Ph.D. 

Duke University Medical Center 

Lucy B. Roarke, M.D. 

Children’s Hospital of Philadelphia 

University of Pennsylvania 

Bruce R. Rosen, M.D., Ph.D. 

Massachusetts General Hospital 

Steven Rosenfeld, M.D., Ph.D. 

University of Alabama at Birmingham 

Susan C. Rossi, Ph.D., M.P.H. 

National Cancer Institute 

Tom Roszman, Ph.D. 

University of Kentucky Medical Center 

Roundtable Roster 95 
David Rowitch, M.D., Ph.D. 

Dana-Farber Cancer Institute 

Harvard Medical School 

James T. Rutka, M.D., Ph.D., F.R.C.S.C. 

The Hospital for Sick Children, Toronto 

John H. Sampson, M.D., Ph.D. 

Duke University Medical Center 

Gail Segal 

North American Brain Tumor Coalition 

American Brain Tumor Association 

Dennis Shrieve, M.D., Ph.D. 

University of Arkansas for Medical Sciences 

Malcolm A. Smith, M.D., Ph.D. 

National Cancer Institute 

Evan Y. Snyder, M.D., Ph.D. 

Boston Children’s Hospital 

Harvard Medical School 

Harald W. Sontheimer, Ph.D. 

University of Alabama at Birmingham 

Elizabeth Stevenson 

North America Brain Tumor Coalition 

Philip J. Tofilon, Ph.D. 

University of Texas M.D. Anderson Cancer 

Center 

Arthur W. Toga, Ph.D. 

University of California, Los Angeles 

School of Medicine 

Dianne S. Traynor 

Pediatric Brain Tumor Foundation of the 

United States 

Annabelle Uy, M.S. 

National Cancer Institute 

Richard Vallee, Ph.D. 

University of Massachusetts Medical School 

Michael D. Walker, M.D. 

National Institute of Neurological Disorders 

and Stroke 

Jeannine Walston 

National Coalition for Cancer Survivorship 

Susan L. Weiner, Ph.D. 

North American Brain Tumor Coalition 

Carol J. Wikstrand, Ph.D. 

Duke University Medical Center 

Albert Wong, M.D. 

Kimmel Cancer Center 

Thomas Jefferson University 

Roy S. Wu, Ph.D. 

National Cancer Institute 

Mark Yarborough, Ph.D. 

University of Colorado Health Sciences 

Center 

Richard J. Youle, Ph.D. 

National Institute of Neurological Disorders 

and Stroke 

Jeanne Young 

The Childhood Brain Tumor Foundation 

John S. Yu, M.D. 

Maxine Dunitz Neurosurgical Institute 

Cedars-Sinai Medical Center 

W.K. Alfred Yung, M.D. 

University of Texas M.D. Anderson Cancer 

Center 

96 Report of the Brain Tumor Progress Review Group 
NIH Pu

blication Number 01–4902

November 2000 

T491