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 (BT- PRG) 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 BT- PRG 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, site- specific 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 Even the term brain tumor, which suggests a single type of tumor, can be misleading. Brain tumors represent a unique challenge in There are a bewildering variety of central that they affect the organ that is the essence nervous system tumors; the World Health of the “self.” Furthermore, because each area Organization lists 126. Many of these of the brain serves a different but vital tumors are not, strictly speaking, in the brain function, the therapy that is most effective but arise from structures intimately for other cancers—surgical removal of either associated with that organ, such as tumors of the entire organ or the tumor with a generous the covering membranes (meningiomas) and surround of normal tissue—cannot be used adjacent cranial and paraspinal nerves to cure brain tumors. Unfortunately, most (schwannomas). Brain tumors range from brain tumors are relatively insensitive to benign (most meningiomas) to highly other cancer treatment, including radiation aggressive (glioblastomas). They affect both and chemotherapy. adults and children (although the distribution of tumors varies) and are often Coupled with the difficulty in treating brain highly resistant to treatment. tumors is the unique biology of the brain: The term brain cancer is also misleading. • Brain tumors occur in an organ that is Most cancers that arise elsewhere in the enclosed in a bony canal that allows little body cause damage by metastasizing to room for growth of the tumor without other organs (including the brain). Primary compressing and damaging normal brain tumors, however, rarely metastasize, brain. although they may widely infiltrate the • Many brain tumors extensively invade nervous system. Conversely, many cancers normally functioning brain, making metastasize to the brain, making metastatic complete surgical removal impossible. brain tumors much more common than • In their early stages, brain tumors are primary brain tumors. protected behind a blood-brain barrier; even when this barrier is disrupted in the Throughout this document, the term brain bulk of the tumor, infiltrating tumor cells tumor is used to refer to all tumors that grow at the growing edge remain protected. inside the skull. The issues discussed in this • Disruption of the blood-brain barrier document, however, also extend to tumors leads to edema, which the brain tolerates growing within the spinal canal. poorly because of the limited intracranial space and the lack of lymphatics to rid STRUCTURE AND PROCESS OF THE itself of the products of edema and other PRG MEETING debris. • The brain itself is rich in expressed For the reasons described in the introduction genes and therefore is a fertile field for to this report, the Brain Tumor Progress the growth of both primary tumors and Review Group (BT-PRG) required input metastases. from participants with much more diverse • The brain and brain tumors appear to be expertise than was needed in previous less susceptible to attack by the immune PRGs. In addition to experts on cancer system than are tumors in other organs. biology and genetics, the BT-PRG required

Report of the Brain Tumor Progress Review Group 3 expertise in neurobiology, including areas into an overall hierarchy. Although all of the such as progenitor cells, cellular migration, priorities included in the appendices are and blood-brain barrier function. Clinically, important and meritorious, some arose in expertise was required from both oncology multiple breakout sessions and therefore and the clinical neurosciences, including appear to be of overarching importance. This neurosurgery and neurology. In addition, to report delineates those priorities considered ensure inclusion of the wide diversity of by the BT-PRG to be overarching. The brain tumors, breakout sessions were held appendix contains the full reports of the not only for those topics that apply to all individual breakout sessions and their solid tumors, including brain tumors, but priorities. also (different from other PRGs) for specific types of brain tumors (i.e., intraaxial tumors, This report is divided into two sections. extraaxial tumors, pediatric tumors, and Section I, “Scientific Priorities,” describes metastases). A total of 16 breakout groups the overarching priorities in both the basic were therefore convened (see box). Each and the clinical sciences. These scientific participant attended three breakout sessions. research priorities are hypothesis driven. To meet them will require the scientific The participants in each of these 16 breakout resources described in Section II. The sessions were asked to identify three resource priorities in Section II can be important research priorities in their considered as hypothesis generating in that assigned areas. It was recognized that it their development will generate hypotheses might not be possible to place all of the for further research. research priorities formulated by the groups

STRUCTURE OF THE BT-PRG BREAKOUT GROUPS Basic Biology Clinical Biology Specific Tumors • Models • Detection, Diagnosis, • Extraaxial Tumors • Cancer Biology and and Prognosis • Intraaxial Tumors Etiology • Epidemiology, • Pediatric Tumors • Neurobiology: Prevention, and • Metastases Progenitor Cells Outcomes • Neurobiology: •Imaging Migration and • Radiation Biology Trafficking • Therapeutic Targeting: • Cancer Genetics Blood-Brain Barrier, • Tumor Immunology Gene Therapy, and Vascular Biology • Treatment

4 Report of the Brain Tumor Progress Review Group SECTION I: SCIENTIFIC PRIORITIES The biology of brain tumors is distinct from that of many other human tumors. Although Three separate sets of breakout sessions tumors are named as though their lineage addressed the scientific priorities. One set were understood (e.g., astrocytoma from was devoted to fundamental biology and astrocytes), the cells of origin for most included sessions on models, neurobiology human brain tumors remain enigmatic, of progenitor cells and of cellular migration complicating the interpretation of data that and dispersal, cancer biology, require a comparison between brain tumor immunobiology, and cancer genetics. cells and their “normal” counterparts. Another set of sessions was related to Highlighting these issues are childhood clinical issues, ranging from detection and brain tumors, especially primitive diagnosis to treatment and outcomes. A third neuroectodermal tumors that arise during set was devoted to specific tumors. Several brain development. Insights into the normal overarching scientific priorities emerged and aberrant regulation of from all of these sessions and are described neurodevelopmental genes may be here. significant in understanding the etiology of both childhood and adult brain tumors. Basic Biology Likewise, elucidating the genetic alterations in brain tumors may yield new insights into Brain tumors are phenotypically and brain development. Achieving significant genotypically heterogeneous. Significant advances in the diagnosis, prognosis, gaps exist in current understanding of the therapy, and prevention of brain tumors molecular pathways involved in the genesis, requires unraveling and understanding many progression, and biological and clinical aspects of the cellular and molecular biology behavior of brain tumors. Brain tumors are of brain tumors and their interactions with unique among human cancers because of normal brain elements. These advances must their complex interaction with the brain proceed along a number of different fronts itself, which greatly complicates the use of and will require the interaction of several existing therapies as well as the disciplines in order to achieve the greatest development of novel ones. chance of success (see “Communication” in Section II of this report). A cardinal feature of the most common malignant brain tumors—their diffuse Many of the priorities generated by the infiltration into the surrounding breakout sessions of the BT-PRG brain—presents substantial barriers to the overlapped, particularly those concerning effective delivery of therapeutic agents and needed resources (see Section II). The increases the possibility of therapeutic highest scientific priorities in basic biology toxicity to a vital organ whose function identified by such overlap are as follows: greatly affects the patient’s quality of life. Other obstacles to effective therapy include • Understand the complex biology of brain the blood-brain barrier and the difficulties it tumors, both primary and metastatic, and creates for therapeutic delivery, as well as their interaction with normal brain the relative lack of information on the elements as they relate to oncogenesis, unique immunological aspects of brain progression, tumor cell dispersal, and tumors and the cerebral environment. heterogeneity.

Report of the Brain Tumor Progress Review Group 5 — Define the genetic changes and tumors. Other suggested etiologies, such as molecular pathways involved in nonionizing radiation (e.g., from cellular brain tumor initiation and telephones or high-tension wires), viral maintenance. agents, household chemicals, or foods, have — Characterize the interactions of brain not been established as causal. In addition, tumor cells with the normal brain. little is known about the interaction of • Provide a detailed molecular genetic factors and environmental toxins in classification of the cells of origin for the genesis of brain tumors. distinct tumor types and define their lineage associations, as well as the signal Because identification of the risk factors for transduction pathways that regulate cell brain tumors may aid prevention and suggest fate and the mechanisms by which the effective treatments, high-quality local environment of the brain influences epidemiological studies are extremely cell migration and differentiation. important. Factors that inhibit • Understand genotypic influences on epidemiological studies include the phenotypic behavior, tumor type, age at relatively small number of patients affected onset, anatomical position, cell of origin, by brain tumors and the large number of and cellular biology. histopathological types of these tumors. • Isolate the genes that predispose to These factors complicate the design of human brain tumors and understand their research protocols and limit the statistical relationship to the genes that regulate power of the data collected. In addition, normal development. existing tumor registries are neither linked • Identify the genes that regulate patients’ nor structured to facilitate the collection of responses to chemotherapy and large numbers of samples for meaningful radiotherapy and those that mediate epidemiological research. Important tumor chemoresistance and epidemiological scientific priorities, radioresistance. therefore, include the following: • Characterize both central nervous system and systemic immune responses in • Support the linking of existing databases patients with brain tumors. to provide larger numbers of samples for • Understand the blood-brain barrier and epidemiological studies. its regulation. • Expand and enhance databases to • Understand the mechanisms underlying include all primary brain and spinal the spread and establishment of tumors—malignant and nonmalignant, metastases in the central nervous system. adult and pediatric—and to have the flexibility to accommodate new Epidemiology histological and molecular classifications of tumors. Little is known about the epidemiology of • Develop epidemiological studies of brain tumors. Germ line mutations (familial patients’ susceptibility to the toxic brain tumor syndromes) account for no more effects of current treatment modalities than 7% of patients. The only unequivocally and investigate risk and protective established risk factors for nonfamilial brain factors with study designs that tumors—therapeutic irradiation to the brain incorporate biological measures. and chronic immunosuppression (e.g., • Use validated animal models (see AIDS)—are also infrequent causes of brain “Models,” Section II) to study the

6 Report of the Brain Tumor Progress Review Group potential causal factors of brain tumors histological phenotype alone. Once such and of treatment-induced neurotoxicity. techniques become possible and practical, molecular profiling could be accomplished Detection and Diagnosis by tissue analysis or imaging. In the future, molecular markers could also form the basis Because brain tumors are an extraordinarily for screening at-risk individuals or heterogeneous group of lesions, accurate populations. In light of such possibilities, the diagnosis is essential to proper management. following priorities in the detection and Current imaging techniques provide a diagnosis of brain tumors were identified: sensitive means for delineating the anatomical features of brain tumors but have • Develop a molecular- and imaging-based not provided an effective means for early classification scheme for brain tumors detection. Early detection could also be that can be used to predict tumor complicated by the ethical problems created behavior and to guide treatment by presymptomatic diagnosis of tumors for decisions more accurately and which there may not be effective treatment, objectively than is possible with current and in an organ whose proper function is histopathological methods. essential to quality of life. Nonetheless, early • Develop techniques that can reliably detection of brain neoplasms, particularly in detect brain injury related to tumor or the pediatric population, where these lesions treatment and use such techniques to are often treatable, could be facilitated by assess the efficacy of neuroprotective appropriate education of pediatricians, interventions. parents, school officials, and other caregivers. Treatment

The diagnosis of brain tumors is currently Treatment options for patients with brain based on histological examination of brain tumors have been limited and, for most tumor tissues after radiological types of tumors, have provided only modest characterization and surgical biopsy. These benefits. Some of the likely reasons for these approaches are successful in classifying and limitations (see “Introduction”) include the grading most cases, but in many situations unique structural and physiological aspects they do not allow accurate prediction of of the central nervous system, especially its therapeutic responses or of prognosis. The vulnerability to damage from many therapies situation may be further complicated by the as well as from neoplastic processes small size of some diagnostic biopsy themselves. Research in the treatment of samples. There is therefore a critical need to brain tumors has been hampered by the lack improve the diagnosis of brain tumors in of clinically predictive model systems; by a order both to improve current therapeutic minimal understanding, until quite recently, management strategies and to form a basis of fundamental tumor biology; and by a for the evaluation of novel approaches. narrow range of available therapeutic agents for testing that have had little expected The ability to characterize tumors specificity for brain tumors. The major comprehensively at the molecular level challenge for the future is to develop more raises the possibility that diagnosis could be effective techniques to treat brain tumors based on molecular profiling, either alone or without damaging the brain. with histological examination, rather than on

Report of the Brain Tumor Progress Review Group 7 Marked progress is currently being made in • Develop therapies that are less toxic than dissecting the molecular mechanisms of existing therapies to both the mature and neoplasia in the brain and elsewhere. These the immature nervous system. advances are enabling the rapid identification of relevant molecular targets, Outcomes and the result is a vast array of potential therapeutic approaches and agents in the Traditional outcome measurements used in development pipeline. At the same time, brain tumor studies have included overall advances in neuroimaging are raising the and recurrence-free patient survival and, in tantalizing possibility of clinically assessing some instances, radiological response to the capacity of an agent to alter its intended therapy. Such measurements, however, target. It therefore seems reasonable to largely ignore crucial issues relating to expect an improved rate of success in quality of life and biological endpoints of research on the treatment of brain tumors. response. These issues are of particular Because the special characteristics of these importance in tumors for which effective tumors will continue to present problems therapies may not exist and in pediatric and challenges, however, the following tumors, for which effective tumor control priorities were identified: may be associated with significant long-term morbidity. For these reasons, there is an • Facilitate the development of novel immediate and crucial need for better therapeutic agents and approaches for measurement tools and surrogate markers to adult and pediatric brain tumors. These assess patient quality of life and tumor approaches should include, but not be response to therapy. Such outcome markers limited to, chemotherapeutic, would facilitate the assessment of immunologic, antiangiogenic, genetic, neurotoxicity, thereby providing an and viral agents. opportunity to discard potentially neurotoxic • Increase knowledge about the therapies sooner. They would also facilitate mechanisms of existing therapies for more accurate assessment of therapeutic both adult and pediatric brain tumors. response, thereby allowing effective • Improve the therapeutic index of new therapies to be continued while ineffective agents that are specifically relevant to therapies are discontinued. The following the central nervous system. priorities were therefore identified: • Enhance the therapeutic ratio for radiation therapy for brain tumors. • Improve techniques for measurement of (Overcome radioresistance of primary quality of life and include such brain tumors; overcome normal tissue measurements in all clinical trials of toxicity such as necrosis/edema and brain tumor. functional deficits.) • Refine the ability to detect response to • Develop novel drug targeting systems existing therapies, such as radiation, and that enhance the uptake by brain tumors to novel treatments, using surrogate of small- and large-molecule diagnostic markers measured either by imaging or and therapeutic agents. in biological fluids (e.g., serum or • Develop clinical consortia for cerebrospinal fluid). immunotherapy that are similar to those • Establish clinical and imaging markers for radiation and chemotherapy. of neurotoxicity from existing therapies,

8 Report of the Brain Tumor Progress Review Group such as radiation, and from novel • The group addressing intraaxial brain treatments. tumors highlighted issues relating to • Extend the use of such markers to low-grade gliomas, primary central preclinical evaluations in animal models. nervous system lymphomas, and germ cell tumors. Specific Tumors • The session on extraaxial brain tumors emphasized the need for studies that Recognizing the remarkable diversity of incorporate careful long-term follow-up human brain tumors and the distinct clinical for these often slowly growing lesions. questions associated with different tumor • The group discussing metastatic tumors types, the PRG members were concerned of the brain made the unique that most of the general scientific sessions recommendation to convene a PRG would concentrate on the more common devoted to the biology of metastasis. tumors, such as malignant gliomas and medulloblastomas, to the exclusion of other The specific priorities from these sessions brain tumor types. To address the possibility are detailed in the individual reports in that research priorities might relate to Appendix A. different types of brain tumors, the PRG convened four special breakout sessions to SECTION II: RESOURCE PRIORITIES focus on particular groups of brain tumors: pediatric brain tumors, intraaxial brain Although the scientific priorities set forth by tumors (excluding malignant gliomas and the BT-PRG varied considerably across the medulloblastomas), extraaxial brain tumors, different areas of scientific and clinical and metastases to the brain. These four investigation, the resources required to special breakout sessions met after the 12 accomplish those priorities were remarkably general scientific sessions had adjourned. concordant. Indeed, nearly all of the five The special sessions included attendees from resource priorities listed below were deemed the earlier, general discussions, thereby essential by most of the participants: allowing important issues from the general sessions to be applied to discussions of the specific tumor groups. 1. Models 2. Tissue banks and databases Remarkably, the research priorities and 3. Genomics and high-throughput needed resources identified by these special screening groups echoed those of the general sessions, 4. Communication although some different emphases were 5. Training placed according to tumor type: These resources can be viewed as hypothesis • The session on pediatric brain tumors generating because they will provide the emphasized clinical problems such as information and abilities to accomplish the the need to study long-term outcomes for scientific and clinical priorities listed in survivors of brain tumors, to investigate Section I. The creation of these resources is the impact of therapies on the deemed essential in order to develop new, developing brain, and to focus on some effective therapies for brain tumors. of the rarer, more primitive tumors occurring in children.

Report of the Brain Tumor Progress Review Group 9 Models Tissue Banks and Databases

Models are central to making the transition Addressing the complex biology of brain from developing scientific concepts to tumors requires innovative tumor banking understanding human tumors within the and characterization facilities with relevant context of the tissues that they affect. and appropriate clinical and radiological Models may be used for therapeutic screens, databases. Tissue banks linked to clinical in preclinical trials, or to study the basic databases are also vital for translating biology of tumors. However, because research discoveries into clinically relevant currently available cellular, tissue, and information. Because current tissue banks animal models do not accurately represent are typically institution based, they are the biology of human brain tumors, it is vital limited in scope and amount of available to: specimens. These banks also process tissues in different ways, and their specimens are • Develop tissue and cell culture systems usually not sufficiently annotated with that replicate the biology of human brain clinical and radiological information. tumors. Because of the rarity of many brain tumor • Create genetically and behaviorally types, including both adult and pediatric accurate models for brain tumors in mice neoplasms, there is a great need for and other animals. organized, interinstitutional approaches to • Generate tissue-based, imaging, and banking and data management of both adult genomic methods to validate and and pediatric neoplasms. compare animal models with their human counterparts. An effective tissue bank or database must do • Improve the availability of the reagents the following: needed to create new animal models of brain tumors, the sophisticated • Collect and bank tissue, blood, technologies used to evaluate and cerebrospinal fluid, and (when available) validate those models, and the animal normal brain from patients with all models themselves. varieties of brain tumors. In particular, attention should be paid to banking To accomplish these priorities, a mechanism pediatric tumors; rarer intraaxial tumors, must be created to support the development such as low-grade gliomas and and validation of model systems that more lymphomas; tumors that follow long accurately reflect the biology of brain clinical courses, such as meningiomas; neoplasms. Although the National Cancer and metastases, when tissue from the Institute (NCI) Mouse Models for Human primary tumor is also available. Cancer Consortium (MMHCC) has been Specialized banks should also focus on established to fund the development of acquiring clinical and radiological mouse cancer models, additional mouse information and tissues from distinct models of the various brain tumors that are populations, such as patients with not addressed through the MMHCC, as well neurofibromatosis 2, who provide as models in other animals, remain high unique opportunities to follow the priorities. 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 throughput screens would allow large submitted to the banks. In this regard, a amounts of information to be gleaned challenge will be to alter the sociology quickly and would facilitate further of data sharing in order to make a translational research toward more tailored concerted shift to a shared, distributed therapeutic approaches. These screens can system. occur at the tissue level ex vivo or, in the • Maintain a comprehensive database of future, at the molecular neuroimaging level relevant clinical and demographic, in vivo. For such large-scale approaches to pathologic, biologic, and therapeutic be functional, considerable emphasis will information on all patients whose tissue need to be placed on bioinformatics support. is banked. Develop links to population The need for high-throughput screening databases to enhance potential technologies was identified by a number of etiological and other epidemiological the different breakout sessions; the highest studies. priorities were the following: • Involve multidisciplinary participation of surgeons, pathologists, scientists, and • Develop high-throughput laboratory other professionals, including approaches to understand gene function neurooncologists, to ensure reliable and and to identify the targets and pathways consistent tissue processing. that are critical to brain tumor biology. • Provide mechanisms to ensure access, on • Develop high-throughput laboratory a competitive and open basis, by approaches to identify the genes and researchers to the material and data in genetic variations that underlie tumor the bank. resistance to chemotherapy and radiation • Employ approved and ethical therapy, as well as the allelic variations methodologies to protect patient that influence responses to therapy in confidentiality and ensure appropriate individual patients. patient consent. • Develop high-throughput laboratory • Feature local and regional facilities and approaches to identify antigens that may facilitate effective communication and be used to further understanding of the collaboration among centers. immunological features of brain tumors • Be supported by ongoing funding, and to develop novel immunological potentially for longer than 5-year therapies. periods, to facilitate study of tumors with • Develop high-throughput neuroimaging long clinical courses, such as approaches for the in vivo meningiomas. characterization of the molecular features of tumors and the surrounding Genomics and High-Throughput brain that could monitor and influence Screening therapies. • Develop the bioinformatics support The explosion of information in genomics, necessary for rapid and accurate analysis together with the promise of similar of data generated via these high- advances on the near horizon in proteomics, throughput approaches. raise the need for technologies that allow • Establish a consortium of brain tumor high-throughput screens of brain tumors and modeling laboratories for the purpose of related specimens (e.g., other tissues from testing novel therapies. patients with brain tumors). Such high-

Report of the Brain Tumor Progress Review Group 11 • Allocate resources for the generation of interinstitutional interactions strongly cDNA microarrays based on the mouse encouraged. The possible extension of such equivalent of the human sequences interactions to the grants review process was identified through the Brain Tumor also deemed an important area for Genome Anatomy Project (BT-GAP). discussion. • Create a mechanism to ensure affordable access to these reagents and models. Because the Center for Scientific Review (CSR) reviews most unsolicited brain tumor Communication grant applications, the brain tumor research community believes that better coordination The PRG Roundtable meeting provided a among the institutes and CSR is needed. unique opportunity for scientists from Improved communication could prevent different disciplines—including cancer brain tumor biology from “falling between biology and genetics, neurobiology, the cracks” among the various review groups immunology, and radiation biology—to that may have relatively few brain tumor meet and discuss brain tumor biology. These biologists. It is anticipated that coordinated stimulating interactions highlighted the efforts by NINDS, NCI, and CSR on the potential for novel insights arising from such referral, review, and funding of brain tumor interdisciplinary interactions. A central goal research applications would facilitate the that emerged from these discussions was the implementation of the national plan for brain need for further communication among these tumor research. various disciplines on the subject of brain tumor biology. Such enhanced Goals for improved communication extend communication would in turn lead to to clinical problems as well. There is clearly interdisciplinary collaborations that would a need for increased dissemination of approach problems in brain tumor research information to patients, as well as to from a unified, and therefore novel, clinicians outside of neurooncology centers, perspective. with regard to the variety of available treatment options. The relatively low It was recognized that one reason for the percentage of patients with adult malignant relative lack of such communication and gliomas who are enrolled in clinical trials collaboration among disciplines has been the may reflect an inadequate knowledge of historically different funding and oversight treatment options on the part of both patients mechanisms that have supported such and physicians. This area of need represents research. For example, neurobiology an ideal opportunity for patient advocacy research is largely funded through the groups to collaborate with physicians to National Institute of Neurological Disorders develop strategies to educate patients and and Stroke (NINDS), whereas cancer clinicians about treatment options, including biology and immunology research is clinical trials, as well as about the generally funded by NCI and other agencies. specialized expertise that is available at Recent attempts to bring together NCI and neurooncology centers. For these reasons, NINDS to address questions in brain tumor the following priorities were identified: research—the BT-PRG, the BT-GAP, and the establishment of a combined NCI- • Establish a set of interactive meetings NINDS Neurooncology Branch—have been involving scientists from different widely applauded and further biological disciplines (cancer biologists

12 Report of the Brain Tumor Progress Review Group and geneticists, neurobiologists, — Encourage funding for immunologists, and radiation biologists) interdisciplinary and translational that focus specifically on important research. issues in brain tumor biology. — Recruit new talent and sustain • Facilitate collaborations among different proven talent in the field of brain disciplines by encouraging tumor research. interdisciplinary grant applications in • Create innovative public and private brain tumor biology and etiology. programs to stimulate promising young • Continue to develop combined programs investigators to choose a career in in brain tumor research from NCI and clinical or laboratory brain tumor NINDS and explore the possibility of research through, for example, tuition revisions in the grant review process for loan payback or forgiveness and brain tumor research. fellowships. • Encourage coordinated activities by • Develop a joint NCI-NINDS campaign advocacy groups toward further to encourage students to pursue education of patients and clinicians interdisciplinary careers in the field of about available treatment options for brain tumor research. brain tumors. • Develop at NIH a model for a joint NCI- NINDS interdisciplinary training Training program in neurooncology at both the basic science and the clinical level. This Achieving the goals for brain tumor research program might include not only training outlined in this report requires an adequately at NIH for 2–3 years, but also additional sized and well-trained scientific and clinical support for the first 3 years of the work force specializing in brain tumor individual’s career as an independent research. Unfortunately, there is a dearth of investigator. basic scientists working in the field of brain tumors, which lacks sufficient numbers of CONCLUSION clinicians who are cross-trained in brain tumor biology and scientists who are aware Although not among the most common of of the problems driving clinical neoplasms, brain tumors are among the most neurooncology research. As is the case for devastating. Mental impairment, seizures, biomedical science in general, there exists a and paralysis afflict the very core of the true crisis caused by the small number of person and have a demoralizing effect on clinician-investigators now entering loved ones. Added to these burdens is the academic medicine. This issue has been knowledge that, for most brain tumors, discussed elsewhere and will not be adequate treatment is not available and the recapitulated here, but its importance should likelihood for long-term survival is poor. In not be underestimated. High priorities for children, even if they do survive, the brain tumor research are therefore as devastating impact of disease and treatment follows: often leaves permanent neurological damage. • Enhance training opportunities and support: 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 Peter T. C. Ho Sandra Rempel Mitchel Berger Susan Hockfield James Rutka Webster Cavenee Mark A. Israel Richard Vallee Rolando Del Maestro C. David James Jeannine Walston Ronald A. DePinho William G. Kaelin Albert Wong Richard A. Fishel Robert L. Martuza Roy S. Wu Henry Friedman Christina A. Meyers W. K. Alfred Yung Candece Gladson Jasti Rao

STATEMENT OF THE PROBLEM • Are the genetic changes and pathways that are required for initiation the same • Brain tumors are highly heterogeneous, as those required for maintenance of both phenotypically and genotypically. the neoplastic phenotype and its • Significant gaps exist in our knowledge biological behavior? and understanding of the genes, genetic • What model systems and approaches changes, and pathways involved in the are required to advance our study of genesis, progression, and biological these multigenetic changes and and clinical behavior of brain tumors. pathways? • There is currently an inadequate • What are the interactions between the understanding of brain tumor biology, brain tumor and the normal brain? particularly as it relates to the complex • How do tumor-brain interactions environment of the brain. contribute to oncogenesis and • The achievement of significant metastasis in the central nervous advances in diagnosis, prognosis, system? therapy, and prevention of brain tumors • “Seed-soil” interactions: How does the will require unraveling and spatial-anatomical site of the tumor understanding the cellular and against its specific genetic background molecular biology of brain tumors and determine the gene expression patterns their interactions with normal brain. and contribute to tumor heterogeneity, biological and clinical behavior, and CHALLENGES AND QUESTIONS therapeutic outcome? • Are there genetic changes and • What are the genetic changes and pathways that are common to different pathways of oncogenesis and brain tumor subtypes? progression that account for the • What pathways, such as signaling, heterogeneity of brain tumors, and how apoptosis, cell cycle, and migration, are can these be studied? involved in the response of brain • Which genes, genetic changes, and tumors to intra- and extracellular pathways are important to the stimuli such as growth factors or redox initiation, maintenance, and changes? progression of brain tumors?

Cancer Biology and Etiology 15 • What are the stem cells and progenitor • Technological barriers: There is an cells of the different brain tumor inadequate application to brain tumor subtypes? biology research of the latest • What model systems and approaches technological advances, such as those are required to advance the study of in genomics and proteomics, structural brain tumor biology and of the biology, chemical biology, and high- interactions between tumor cells and throughput screening strategies. normal brain? • If the genetic changes or lesions that RESEARCH AND SCIENTIFIC initiate cancer are different from those PRIORITIES required for progression and maintenance, could these be targeted in Priority 1: order to develop novel therapies? Understand the complex biology of brain BARRIERS tumors and their interaction with the normal brain as it relates to oncogenesis, • Interdisciplinary barriers: progression, and heterogeneity. — There is poor communication and collaboration between researchers in • Define the multigenetic changes and neurobiology and those in pathways involved in oncogenesis, neurooncology, although expertise and progression, and maintenance of brain advances in each field are essential to tumors, with particular attention to advancing understanding of brain their heterogeneity. tumor biology. • Identify the genes and pathways that — Current infrastructure and systems are differentially involved in tumor do not encourage or facilitate initiation and maintenance. interdisciplinary interaction. • Characterize the interactions of the — In the current grant review process, tumor cell with normal brain interdisciplinary grants that would components as determinants of encourage collaboration are often not heterogeneity, gene expression, reviewed favorably because of the biological and clinical behavior, and existing review criteria. therapeutic response within the context of the specific anatomical sites of the • Tissue resource barriers: Existing brain in which the tumor is located. tumor banks often do not have • Define and characterize the cells of appropriate, relevant information, such origin of different brain tumor as information on diagnosis, biological subtypes. characteristics, natural history, and therapeutic outcome. The banks also Priority 2: often do not collect normal tissue or blood. Develop appropriate model systems for studying brain tumor biology that will • Models: There is a lack of appropriate allow for the following: in vitro and in vivo models and systems with which to study the • Mimic the biological complexity of the complex biology of brain tumors. brain, including brain matrix

16 Report of the Brain Tumor Progress Review Group • Facilitate comparative genetic studies — Have mechanisms in place to in human brain tumors and animal ensure access by researchers to the brain tumor models material and data in the bank. • Provide an interface between tumor — Include local (institutional) or cell and stem cell biology regional centers and encourage • Study interactions and pathways communication and collaboration between brain tumor cells and cellular among centers. components of normal brain — Receive ongoing funding, • Study molecular, cellular, and spatial specifically for longer than 5-year heterogeneity in brain tumors periods, because of the long-term • Study the functional outcome of nature of tissue banking specific genetic lesions • Evaluate novel therapies that target • Establish a centralized molecular specific genes, gene products, and profiling (cDNA and tissue array) pathways resource with a strong bioinformatics component to profile gene expression Priority 3: patterns and genetic abnormalities in different brain tumor types. Such a Develop high-throughput approaches to facility could be located at NCI or understand gene function and to identify NINDS or could be extramural. the targets and pathways that are critical to brain tumor biology and therapy. • Develop the infrastructure and mechanisms to open up RESOURCES NEEDED communication and collaboration among researchers in neuroscience, Priority 1 neurobiology, neurooncology, and cancer biology. Such an infrastructure • Address the complex biology of brain would include: tumors requires innovative tumor — Workshops and specialized banking and characterization facilities meetings among these scientists with relevant and appropriate — New funding mechanisms and databases. These facilities will enable grant review criteria appropriate for the following: interdisciplinary research — Collect and bank tissue, blood, cerebrospinal fluid, and (when Priority 2: available) normal brain from patients with all varieties of brain tumors. Targeted funding is needed for the — Maintain a comprehensive database development of model systems. of relevant clinical and demographic, pathological, biological, imaging, and Priority 3: therapeutic information on tumors. — Involve the multidisciplinary Resources are needed to develop the participation of surgeons, pathologists, following: scientists, and other professionals, including neurooncologists, for tissue • Chemical and combinatorial libraries processing. 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 Frederick F. Lang, Jr. Peter M. Black John Mazziotta Ronald G. Blasberg Sherie Morrison E. Antonio Chiocca Edward A. Neuwelt Pam Del Maestro Sam D. Rabkin Lester Drewes Bruce Rosen Ramon Gilberto Gonzalez Richard Youle

STATEMENT OF THE PROBLEM unique to the brain and that bypass the vasculature.

An important problem in the treatment of At one time, the BBB was not been human brain tumors is posed by the need to considered to present a problem in the deliver therapeutic agents to specific regions diagnosis and treatment of brain tumors of the brain, distributing them within and because early scans of human brain tumors targeting them to brain tumors. The suggested that the BTB was “leaky.” This molecules that might otherwise be effective leakiness is relative, however: as the size of in diagnosis and therapy either do not cross the molecule increases, the rate of the blood-brain barrier (BBB) in the brain movement across the barrier decreases. adjacent to the tumor or do not cross the Accordingly, antibodies that could be used blood-tumor barrier (BTB) in adequate as either diagnostic or therapeutic molecules amounts. Improving our knowledge of the do not cross the BTB in sufficient quantities basic molecular and cellular biology of the to be effective. Anti-sense oligonucleotides, brain microvasculature, which constitutes which could be used either to inhibit the BBB and BTB in vivo, could lead to oncogenic signals or as anti-sense innovative new strategies for drug targeting radiopharmaceuticals to image gene to human brain tumors. expression of the brain in vivo, also do not cross the BTB in sufficient amounts for The magnitude of this challenge stems from activity. Gene therapies, whether of viral or the lack of emphasis on BBB research in nonviral formulations, are often too large to both academic neuroscience and the cross the BTB. pharmaceutical industry. Knowledge of the basic functions of the BBB and research on These problems are substantially greater for cerebrovascular biology lag behind those of the BBB in the brain adjacent to the tumor, neuronal or glial biology. An improved because even small molecules do not readily understanding of the brain vasculature and cross the BBB, which is the site of invasion the BBB will play a crucial role in the of glioma cells into normal brain. development of new therapeutic and Furthermore, the expression of drug-active diagnostic approaches for the treatment of efflux transporters, which are expressed at human brain tumors. In addition, there is a the BBB and the BTB, actively efflux need for novel delivery strategies that are chemotherapeutics from the brain back to the blood and may thereby prevent

Therapeutic Targeting 19 significant distribution of chemotherapeutic they can be improved for patients with brain agents in the brain. It is partly for these tumors. reasons that most of the classical chemotherapeutic molecules that have been Cerebral edema is a serious complication in used to treat cancer outside the central many patients with brain tumors. The nervous system (CNS) are ineffective in the molecular and gene-related mechanisms treatment of brain tumors. underlying the formation of cerebral edema need to be identified. Also needed are more CHALLENGES AND QUESTIONS quantitative methods to measure flux or transfer rate constants as indicators of Chief among the challenges to be addressed vascular permeability in patients and in brain tumor research is limited knowledge experimental animals. We also need to about the basic biology of brain endothelial improve our understanding of how to cells, about the cells of origin and the reverse edema and to better understand the developmental changes in gene and protein mechanisms underlying the effects of current expression in brain and endothelial cells, therapies. and about the proliferative potential, turnover rate, and regional differences of Current in vitro models of the BBB are brain endothelial cells. There is also limited inadequate. Although brain endothelial cells knowledge of the cell interactions among co-cultured with astrocytes have been used brain endothelial cells, tumor cells, and cells to study the BBB, better in vitro models that of hematopoietic origin. The role of retain the phenotype of brain endothelial angiogenesis in tumor development and anti- cells will be valuable, as would an in vitro angiogenesis research are important avenues model of the BTB. Basic research on brain for future studies of brain tumor therapy. tumors would be facilitated by the development of appropriate models that Mechanisms for drug targeting in the brain simulate the human condition in situ. involve going either “through” or “behind” the BBB. Modalities for drug delivery RESEARCH AND SCIENTIFIC through the BBB entail disruption of the PRIORITIES BBB, either by osmotic means or biochemically by the use of vasoactive Priority 1: substances such as bradykinin. The potential for using BBB opening to target specific Develop strategies for delivering both agents to brain tumors has just begun to be small and large molecules to the CNS. explored. Other strategies to go through the BBB may entail the use of endogenous The transport of small molecules might be transport systems, including carrier- enhanced by designing drugs that have mediated transporters such as glucose and affinity for one of the carrier-mediated amino acid carriers; receptor-mediated transporters within the BBB. Alternatively, transcytosis for insulin or transferrin; and drugs that inhibit the active efflux active efflux transporters such as p- transporters may be useful as “co-drugs” to glycoprotein. Strategies for drug delivery mediate the uptake of chemotherapeutic behind the BBB include intracerebral agents that are normally effluxed from brain implantation and convection-enhanced to blood. Tumor-specific agents could be distribution. There is a need to determine used with BBB disruption. Similar which strategies are most effective and how 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 Priority 3: could be developed as molecular “Trojan horses” that bind to endogenous receptor- Develop novel viral and non-viral mediated transporters in the BBB and are strategies for brain tumor gene therapy. transferred across the BBB by this mechanism. Viral strategies include the use of adenovirus, herpes simplex virus, adeno- An important mission for the future, not associated virus, and other virus vectors. To only for brain tumors but for the field of date, investigators conducting trials in neuroscience in general, is the ability to humans have used virus gene formulations “image any gene in any person.” This might administered invasively, through be done with antisense radiopharmaceuticals intracerebral implantation. Work in that are made transportable through the experimental animals, however, has BBB. This is a “barrier” problem, because to demonstrated that both intra-arterial and be successful, an antisense molecule targeted intravenous delivery can be efficacious and at an mRNA molecule within the tumor cell safe. Some of the new conditionally must be transported across not only the BTB replicating virus vectors have the added but also the tumor cell and organelle advantage of virus amplification within the membrane “barriers.” tumor after passage through the BBB, thus increasing the treatment volume. Priority 2: The developments in Priorities 1 and 2 Identify the genes and proteins expressed should be applied to improve the delivery of by the BBB and the BTB. virus and non-virus vectors to tumors and to target the BTB. Current problems include BBB genomics should be considered a high the lack of information on the role of the priority. Because only very abundant BBB- immune system in limiting virus replication, specific transcripts will be detected with enhancing tumor rejection, and potentially whole-brain gene microarrays, BBB causing brain inflammation. Limitations also genomics research needs to start with the exist in the methodologies available for initial isolation of brain capillaries from targeting specific tumor cells in order to animal or human brain, both normal and minimize potential toxicity to normal brain tumor derived. Comparison of capillaries and vasculature. Studies have demonstrated from normal brain and brain tumor can help the synergistic effects of virus vectors with to elucidate the tissue-specific gene other modes of therapy, such as expression at the BTB and distinguish it radiotherapy, chemotherapy, and from the tissue-specific gene expression at immunotherapy, but to date these the BBB and normal brain. The elucidation approaches have not been applied in of the pattern-specific tissue expression at humans. 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.

Therapeutic Targeting 21 RESOURCES NEEDED • Novel mechanisms of tumor angiogenesis, invasion, cell adhesion, Priority 1 metastasis, and antigen presentation

The development of novel drug targeting Priority 3 systems in the brain that enhance brain tumor uptake of either small- or large- Development of vectors and strategies molecule diagnostics or therapeutic for gene/viral delivery to brain tumors, molecules requires the following: taking into account the unique character of brain vasculature, extracellular space, and • Inclusion of lipid-soluble drugs that cell diversity, will require the following: penetrate the BBB and of brain tumors in industrial and government antitumor • Novel adenovirus, herpes simplex drug development programs. virus, adeno-associated virus, or other • Novel forms of BTB disruption virus vectors that specifically target • Drugs that access BBB carrier- tumor cells in the brain and do not mediated transport systems cause brain toxicity • Drugs that inhibit BBB active efflux • Virus or non-virus vectors that target transporters such as p-glycoprotein brain tumors upon intraarterial or • New vectors (ligands) that are intravenous administration. Such transported across the BBB by strategies may utilize the ability of receptor-mediated transcytosis systems, some virus vectors to cross the brain which can act as “molecular Trojan vasculature and specifically multiply horses” for transporting drugs across within the tumor or may follow the the BBB and BTB development of novel BBB/BTB drug targeting systems. Priority 2 • Vectors or molecules that specifically target the tumor vasculature without Isolated brain capillaries from either animal harm to the normal brain vasculature or human brain and human brain tumor • Strategies that utilize the above vectors should be used as the starting point for in combination with radiotherapy, preparing BBB-specific gene arrays and chemotherapy, or immunotherapy cDNA libraries from BBB and BTB. BBB gene-specific proteomic programs can also The NCI and the NINDS are urged to adopt be developed in parallel. The focus on these all three of these priorities, as they are genomics or proteomic programs should be interconnected. Gene and viral therapy, use molecular-based strategies for investigation of recombinant proteins, monoclonal of the following: antibodies, or antisense therapy may be successful in patients with the adaptation of • Tissue-specific gene expression of the novel BTB drug targeting systems applied to BBB of normal brain brain tumors. However, the discovery of • Differences in capillaries perfusing novel BBB drug targeting systems will be normal brain BBB and tumor accelerated by the classification of the capillaries (BTB) tissue-specific gene expression at the BBB • New endogenous BBB or BTB through a BBB genomics program. Further, transporters for targeted drug delivery the use of any biological agent for brain to brain tumors 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 Faith G. Davis Roger Packer Jaclyn A. Biegel Lisa DeAngelis Roy A. Patchell Peter M. Black Pam Del Maestro David Ramsay James Boyette Stuart A. Grossman Lynn A. Ries Pim Brouwers Alison Hannah Lucy B. Rorke Greta Bunin Bruce R. Korf Malcolm Smith Peter Burger Craig Lustig Michael Walker R. Edward Coleman Ravi Menon Mark Yarborough

STATEMENT OF THE PROBLEM patients and physicians would hope and need. Current imaging techniques provide Brain tumors are a heterogeneous group of meticulous anatomical delineation and are central nervous system neoplasms that arise the principal tools for establishing that within or adjacent to the brain. Some are neurological symptoms are the consequence curable by surgical resection, but many of a brain tumor. cannot be eradicated by current treatments, and, when they are, disabling neurological CHALLENGES injury often ensues. Moreover, the location of the tumor within the brain has a profound Detection effect on the patient’s symptoms, surgical therapeutic options, and the likelihood of Early detection has not been an area of obtaining a definitive diagnosis. The interest or focus in neurooncology. Because location of the tumor in the brain also early treatment for many types of brain markedly alters the risk of neurological tumors does not improve quality or prolong toxicities that alter the patient’s quality of length of life, early detection strategies have life. not been a priority and their use may not be ethical. In this respect, brain tumors are At present, brain tumors are detected by different from cancers of the breast, prostate, imaging only after the onset of neurological and colorectum, for which screening symptoms. No early detection strategies are strategies are now broadly used in healthy in use, even in individuals known to be at populations. Moreover, because the causes risk for specific types of brain tumors by of brain tumors are not known, it is not yet virtue of their genetic makeup. Current possible to identify special populations that histopathological classification systems, are at increased risk due to environmental or which are based on the tumor’s presumed occupational exposure. cell of origin, have been in place for nearly a century and were updated by the World Imaging, the obvious screening strategy for Health Organization in 1999. Although brain tumors, is extraordinarily costly, satisfactory in many respects, they do not especially given the relative rarity of brain allow accurate prediction of tumor behavior tumors in comparison with breast or prostate in the individual patient, nor do they guide cancer. Genetic testing, a second option, is therapeutic decision-making as precisely as 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 biopsies are feasible. Occasionally a brain modality is not yet a reality for sporadically tumor is treated in the absence of a occurring brain tumors, which by far histopathological diagnosis because its constitute the majority of brain tumors. location precludes safe sampling. Hence, the question arises as to whether there is a role for early detection strategies in Another limitation of the current neurooncology. histopathological basis of brain tumor classification is the inability to accurately Detection can also be defined to include predict tumor behavior or response to prompt diagnosis in symptomatic patients, therapy . Tumors that look similar may early recognition of tumor recurrence in behave quite differently, and conversely, previously diagnosed or treated patients, and tumors that look quite different may behave the ability to distinguish between recurrence identically. Currently, when and radionecrosis. In pediatric populations, histopathological diagnosis is augmented by early symptoms of brain tumor can be clinical and radiographic features such as misdiagnosed as migraine, school phobia, patient age and tumor enhancement, anorexia, or other common pediatric prognostication for survival in individual problems. In very young children, the patients improves but remains inexact. symptoms of brain tumor may be dismissed Predicting response to treatment by as minor developmental delays. An intense histologic, clinical, and radiographic features educational effort is required to ensure that therefore remains elusive. children as well as adults receive prompt and thorough neurological assessment for Given the rapid advances in gene expression lingering symptoms. Imaging methods need profiling, the achievements in sequencing to be able to identify early recurrence and to the human genome, and the continuing distinguish recurrent disease from other revolution in brain imaging, the question pathologies. arises: What is the potential for molecular characterization and advanced imaging, Diagnosis and Prognosis alone or in combination, to augment or replace current histopathological diagnosis The current histopathological approach to and tumor classification in neurooncology? the diagnosis and classification of brain More important, what is the potential of tumors is satisfactory in many respects. In these approaches to predict tumor behavior virtually all instances, brain tumors can be and sensitivity to treatment? These accurately placed into broad diagnostic possibilities are especially exciting because categories, such as gliomas, meningiomas, there are already suggestions that specific or metastases. Within these categories, genetic alterations in glial tumors may however, some tumors are not further predict survival outcomes after specific classifiable; concordance in histological therapies. diagnoses between pathologists is sometimes poor; and tissue samples, when A further exciting opportunity afforded by small, render confident classification advances in molecular medicine and difficult. Increasingly, tissue samples are imaging might be the ability to predict small because stereotactic biopsy procedures response to existing and novel therapies, and are the preferred means to establish a to do so soon after administering the diagnosis of brain tumor. In addition, when intervention. The ability to streamline the the tumor is located deep within the brain or assessment of therapeutic maneuvers would adjacent to eloquent cortex, only stereotactic permit ineffective therapies to be discarded

Detection and Diagnosis 25 quickly. This would be especially welcome Corollary: Refine the ability to predict to patients, who perceive that the evaluation response to existing treatments so that process is slow, inefficient, and imprecise. patients receive active agents prescribed Having an earlier endpoint by which to optimally, and do not receive toxic declare a therapy ineffective would address ineffective therapies. Molecular markers or these important concerns. Moreover, early imaging signals may have the potential to identification of effective therapies quickly accurately predict response. resets the clinical research agenda to include quality of life as well as efficacy. Priority 3:

RESEARCH AND SCIENTIFIC Identify serum markers of individual PRIORITIES brain tumor types in preparation for screening programs in at-risk individuals The successful achievement of the following or in populations. Screening, using serum priorities will require advances in brain markers, will be important and ethical tumor imaging and genetics and will have only when it is clear that early treatment important implications for brain tumor unequivocally improves patient outcomes. treatment. epidemiology, and outcomes. RESOURCES NEEDED Priority 1: Tissue banks linked to clinical databases are Develop a molecular- and imaging-based needed for both pediatric and adult brain classification for brain tumors that is tumors of all types. Tissue banks should capable of predicting tumor behavior and include both paraffin-embedded and frozen guiding treatment decisions more tumor, serum, normal DNA from peripheral accurately and objectively than are blood or buccal mucosa, and, in certain current histopathological methods. instances, cerebrospinal fluid. For frozen tissue, guidelines for quality assurance and Corollary: Investigate whether imaging tissue preparation need to be developed. The methods can be developed to capture the clinical database should contain information tumor’s molecular signature. This is about patient characteristics, family history important because the amount of tumor of brain tumor or unusual cancer tissue available at diagnosis may be limited, susceptibility, imaging features (including and tissue is not available for serial sampling tumor location), therapy administered, after therapy. response to therapy, and survival.

Priority 2: A decentralized banking model is envisioned. Public and professional Refine the ability to detect response to educational efforts will be required to ensure novel treatments so that ineffective that both common and rare brain tumors are therapies can be discarded quickly while submitted to the banks. Large numbers of active compounds are evaluated fully in samples will be important to sustain a clinical trials that assess quality as well as concerted research effort that can address the length of life. Non-anatomical magnetic heterogeneity of these diseases and the many resonance signals, rather than change in scientific questions that will arise. When tumor size, may have the potential to available, serial samples should be banked accurately detect early response. 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 Fred Hochberg David Ramsay Pim Brouwers Peter Inskip Lynn A.Ries Greta Bunin Carol Krutchko Lucy B.Rorke Peter Burger Minesh Mehta Libby Stevenson Faith G.Davis Raymond Mulhern Lisa DeAngelis Scott Pomeroy

EPIDEMIOLOGY few are being pursued through funded studies. Statement of the Problem Many previous epidemiological studies on Gaps in the fundamental understanding of primary brain tumors have significant brain tumors, from basic biological methodological flaws. Methodological interactions to epidemiology, hinder issues themselves warrant investigation to systematic approaches to prevention. advance the field. Questions that need to be Although research exploiting new molecular addressed include how to assess recall bias and genetic technologies is attracting among study subjects who may have scientists and funds, epidemiological cognitive impairment; what types of information about primary brain tumors exposures for which interview data and the remains scarce. The absence of high-quality potential for recall bias may be strong epidemiological studies is an impediment to enough to result in spurious associations; understanding who and how brain tumors how the interval between exposure and arise in both children and adults. interview may affect recall bias; and whether there are feasible sources of control groups Challenges and Barriers in the United States other than the current approach of random-digit dialing and The histopathological variability in brain interviews with hospital patients. tumors and the relatively small numbers of persons affected complicate the design of Most registries collect data only on research protocols and historically have malignant tumors, as defined by the limited the statistical power of studies. International Classification of Diseases, 9th Existing tumor registries and surveillance Edition (ICD-9). That registries are limited systems (including the Surveillance, to malignant tumors artificially constrains Epidemiology, and End Results [SEER] epidemiological understanding of brain Program and the North American tumors. For example, the just-revised Association of Central Cancer Registries classification system used by all cancer [NAACCR]) are not linked or structured to registries now codes juvenile pilocytic allow rapid case ascertainment or case astrocytomas as benign, and therefore sample sizes adequate for meaningful registries—including SEER—are likely to epidemiological research of all brain tumor stop collecting data on these tumors. Brain types. Although promising epidemiological tumor specialists include and treat all clues have been uncovered in recent years, neoplasia of the central nervous system as

28 Report of the Brain Tumor Progress Review Group cancer, and the rationale for including all Priority 2: brain tumors in population-based surveillance systems has been well Target funding to support basic science documented. and population-based human studies to evaluate leads on animal Better surveillance tools are critical to neurocarcinogens, such as exposure to facilitate epidemiological research. Two nitrosamines, viral agents, and avenues of epidemiological investigation are polymorphisms. For known animal especially compelling. In pediatrics, carcinogens, molecular exposure mechanisms are in development for a measures are needed to allow direct surveillance system that routinely collects exposure measures for human studies. biological samples of blood and tumor. A similar system is needed for adult tumors. Priority 3:

Research and Scientific Priorities Investigate the epidemiology of neurotoxicity and other toxic effects of Priority 1: treatment, such as what makes some patients susceptible and what exerts a Enhance and expand the existing protective effect. infrastructure for a surveillance database that does the following: Resources Needed

• Includes all primary brain tumors • Database of household carcinogens. (malignant and nonmalignant, central A database listing the major household nervous system and extraaxial sources of known carcinogens (e.g., • Is designed with enough flexibility to dry-cleaned clothing, oven cleaner, accommodate new histological and specific types of paints, weed killer), molecular classifications of tumors including neurotoxins and • Gives individual investigators access to neurocarcinogens, would be valuable rapid case ascertainment for studies for both brain tumor and cancer that require questionnaires, tissue epidemiology in general. samples, pathological review, and • Training. Training in epidemiological pooling of results to increase sample methods is needed for researchers size. involved in etiological and outcome studies, including neurooncology and SEER and state registries capture 50% or neurosurgery residents. more of neuroepithelial tumors, and extraaxial tumors can be captured only PREVENTION through a central brain tumor registry. Approximately 52% of “quality” registries Statement of the Problem cover the U.S. population. If definitions were changed by consensus, data from Although the literature and the current diverse sources could be integrated into the National Institutes of Health (NIH) research database of the National Cancer Institute and portfolio hold almost no information other databases. 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 OUTCOMES fruit and vegetable intake or maternal use of vitamin supplementation, particularly Statement of the Problem folates, during pregnancy may reduce tumor The endpoints of survival and disease-free development. Other studies suggest a survival, which traditionally have been used protective role for allergic conditions and to assess outcome in patients with cancer, selected infectious diseases in adult tumors. fall painfully short as measures of success in If these isolated results can be replicated and treating brain tumors. From the perspective clarified and the underlying biological of patients and families, “outcome” is a mechanisms understood, intervention and multidimensional, daily reality, and quality prevention strategies may become feasible. of life can be at least as important as survival. So, too, assessment of quality of Challenges life is increasingly used to evaluate the risks and benefits of new treatments. At this juncture, not enough is known about the basic epidemiology of primary brain Researchers who are not directly involved in tumors to guide research initiatives. For this patient care may lose sight of the importance reason, the most pressing challenge is to of the functional impact of brain tumors and acquire data that will drive scientific their treatment on survivors and the families inquiries in prevention. who care for them. Because the current treatment armamentarium has little to offer Research and Scientific Priorities many patients with brain tumors, saving a life can be a considerable achievement. Priority 1: Saving a life without considering future constraints on how life can be lived, Because of the paucity of data and ideas however, may offer an unacceptable about prevention, a request for proposals outcome. Parents want to normalize life for should be issued to stimulate new an affected child, and adult patients want to research approaches. weigh the functional risks they face with each treatment option. Priority 2: To allow patients and parents to make more For a subset of brain tumors, some informed treatment decisions, clinicians information is available to suggest fruitful need more information on the expected research directions. For example, it may functional outcomes of disease and be feasible to explore the prevention of treatment. Such assessment data can also certain familial cancers, such as contribute to the drug approval process, neurofibromatosis or von Hippel–Lindau when the survival benefits of two treatments syndrome. In addition, data from patients are not substantially different. Finally, treated in pediatric cancer cooperative greater understanding of the impact of groups may yield insights about treatment can lead to interventions that will prevention for patients at risk of second allow parents and adult patients to primary tumors resulting from previous rehabilitate damaged functioning and cancer treatment. 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 Research and Scientific Priorities trials. This lack places a serious limitation The goals in the area of outcomes are to be on the ability to weigh the risks and benefits able to predict the impact of the tumor and of new therapies and to develop strategies to treatment on a patient’s functional status and improve functional outcomes. In this to achieve the best possible outcome. context, “function” includes neurocognitive Routine functional assessments and status, symptoms, ability to perform interventions are necessary to improve activities of daily life, and psychosocial patients’ functioning and quality of life and status. Another important but neglected should become the standard of care for aspect of assessment and intervention is the patients with primary brain tumors. impact of brain tumor diagnosis and treatment on families. Because families are Priority 1: the primary caretakers of patients with brain tumors, families’ functioning can have a Identify the pathogenesis of the injury profound and direct impact on patients’ related to the tumor (e.g., rapid versus functioning and quality of life. slow growth, site of the tumor), treatment, and comorbid processes (for example, Challenges and Barriers those involving the neuroendocrine and vascular systems and cytokines). To do A major barrier to the conduct of functional this, the following are necessary: assessments is a negative attitude among clinicians. Some feel that it should be • Correlate patient demographic sufficient for a treatment to avert a patient’s characteristics, imaging, and death. Some clinicians interpret as cognitive/quality of life assessments. presumptuous patients’ wishes to have • Develop animal models in tandem with maximum levels of functioning and minimal human studies. damage to the central nervous system and • Identify markers for patients at risk of loss of function. Further, clinicians may feel developing toxic effects (e.g., the defensive when faced with a patient’s apolipoprotein E genotype). serious or unexpected functional deficits. • Develop and assess drugs that might Finally, clinicians may be unfamiliar with offer neuroprotection during primary the assessment process and may cancer therapy. inappropriately feel that assessment is too costly and burdensome for patients. Priority 2:

To incorporate functional assessments into Design and evaluate innovative the design of clinical trials, two things are interventions to ameliorate undesirable needed: symptoms and functional deficits. Studies should include the following: 1. Criteria to determine which trials may be suitable (functional assessments are • Empirical investigations of what not an appropriate component of all works—pharmacologic, behavioral, clinical trials) cognitive, or a combination of these 2. Identification of the appropriate time approaches points during a clinical trial for • Mechanism-based interventions administration of the assessments. focused on cytokine antagonists, neurotransmitter agonists, and neuroprotective agents

Epidemiology, Prevention, and Outcomes 31 Priority 3: allow the investigator to select the tools that will evaluate hypotheses Alter primary therapy to reduce toxic related to, for example, memory, effects while maintaining efficacy, such as attention, language, and spatial deficits. conformal radiotherapy, local therapy, and reduced doses of radiotherapy. • Survey successful interventions. A review of cognitive-behavioral and To satisfy third-party payers, in anticipation psychopharmacological interventions of eventual coverage of the cost of such used in other rehabilitation-related interventions, cost-effectiveness should be disciplines, such as special education built into the research design prospectively. and rehabilitative practices related to The efficacy of these interventions should be traumatic (acquired) brain injury, correlated with imaging measures, including dementia and aging, and stroke, should functional magnetic resonance imaging, and be undertaken to determine whether with physiological correlates, such as levels successful strategies might be used of pro-inflammatory cytokines and successfully with brain tumor patients. neuroendocrine markers. This review should be comprehensive and include projects funded and/or Resources Needed conducted through the National Institute of Neurological Disorders and Intra-institutional cooperative research Stroke, the National Institute of Child initiatives, both within and outside NIH, Health and Human Development, the should be fostered to address rehabilitation, National Institute of Mental Health, the education, and medical issues. Several National Institute of Dental and working groups or consensus panels should Craniofacial Research, and other NIH be convened under NIH auspices to and Department of Health and Human accomplish the following: Services institutions, centers, and working groups. Similarly, a review of • Standardize assessment tools. The family support interventions developed tools now used to assess patient for traumatized families should be function are not standardized across conducted to cull potentially effective studies, sites, or patient populations. interventions for families with a Standardized assessment instruments member affected by a brain tumor. will enhance the generalization of findings; if a core of standard content • Develop assessment guidelines. exists, institutions can tailor aspects to Guidelines are needed on what and specific studies. Tools need to be valid, when to assess in different types of reliable, easy to use, and inexpensive clinical trials. Currently, questions to administer. about symptoms such as headaches are asked to determine side effects of A panel of neuropsychologists, treatment, but patients may also be neurologists and patient advocates asked questions such as how they feel should select well established, user- about the symptoms they report. These friendly instruments from the literature questions are important for patient care to form a “practice guideline protocol” but vary dramatically from person to for use in evaluating patients in clinical person and may not be informative in trials. Such a protocol of assessment clinical trials. It would also be helpful instruments can be constructed to 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 James F.Gusella James Rutka Rebecca Betensky Daphne A Haas-Kogen Gail Segal Jaclyn A. Biegel C. David James Jeannine Walston Darell D.Bigner Bruce R.Korf Albert Wong J. Gregory Cairncross Kenneth A.Krohn Richard A.Fishel Greg Riggins

STATEMENT OF THE PROBLEM mutations have been reported (e.g., Turcot syndrome, neurofibromatosis 1 Concerted efforts over the past few years and 2, and Li-Fraumeni syndrome). have shown that brain tumors, like other Family patterns are more commonly major human neoplasms, result from the consistent with the possibility of accumulation of genetic lesions during multigenic inheritance (“soft” but tumor progression. Despite the extensive interacting mutations), modifiers that catalogue of these somatic tumor-associated alter the penetrance or expressivity of lesions, significant gaps exist in our the genes, or epigenetic gene understanding of how such lesions initiate inactivation. the process, how they influence therapeutic • A special feature of many malignant response, and the nature of their biological brain tumors is their innate resistance function. Clearly, such information will be to existing chemo- and required in order to harness the knowledge radiotherapeutic approaches. Little is of genetics for improved diagnostic and known about the genetic mechanisms therapeutic modalities. This is of particular responsible for this resistance. For importance for this group of tumors, given example, the impact of somatic or their unique biological and clinical germline allelic variation on these characteristics and heterogeneity. mechanisms remains to be determined. • Limited information exists on how CHALLENGES AND QUESTIONS specific lesions behave in cells of different lineages thought to represent • Little is known about brain tumor precursors of distinct brain tumor predisposition genes in humans. This types. Such information could be of situation reflects the scarcity of importance in the design of therapeutic specimens, poor record-taking of protocols targeting such lesions. family medical histories, insufficient • Little is known of the interactions clinical and pathological information between predisposing/somatic on the samples, the lethality and late mutations and external or internal onset of many of these diseases, the environmental perturbations, such as inaccessibility of early lesions, and hormonal influences, in utero pedigrees that often do not lend exposures, and workplace carcinogens. themselves to mendelian analysis. In This issue might be particularly rare instances, autosomal dominant relevant in explaining tumor patterns indicative of “hard” primary emergence in different age groups

34 Report of the Brain Tumor Progress Review Group (pediatric versus adult) and their RESEARCH AND SCIENTIFIC distinct clinical behaviors. PRIORITIES • The genetic basis of the unique biological features of brain tumors is Priority 1: largely not understood. This applies to integral and important features such as Isolate genes causing predisposition to invasion, motility, angiogenesis, and human brain tumors. necrosis, as well as tumor progression and maintenance. It is important to search for predisposition • Existing genetic models and associated genes in families with brain tumors as the genomic infrastructure (particularly in primary identifier of genes relevant to brain mice) are inadequate to properly tumors. Families whose members are prone address the genetic and phenotypic to a variety of other tumors may represent aspects of the human diseases. In the additional opportunities to isolate genes that absence of validated, refined models, are also relevant to brain tumor rapid testing of candidate cancer genes pathogenesis. Elucidation of the interaction and their therapeutic approaches is of such genes with environmental agents severely hampered. may also play a significant role in • There is an inadequate compendium of understanding the etiology of brain tumors. gene expression profiles for precursor cells and their lineages and tumor Priority 2: derivatives. Little information exists on the nature of the physical and Identify the genes and genetic variations functional interactions of the gene that underlie tumor resistance to products that are known to play a role chemotherapy and radiation therapy, as in the development of brain neoplasia well as the allelic variations that influence with other cellular components. responses to therapy in individual Moreover, genome-wide genotypes patients. have not been collected and so have not been tested for their correlation Priority 3: with tumor type or behavior. • There exists a strong need for the Understand genotypic influences on development of genetic screens that phenotypic behavior, tumor type, age at will permit tumorigenesis. These onset, anatomical position, cell of origin, screens need to be conducted on both and cellular biology. the organism and cell levels. The latter will be depend on the development of Priority 4: in vitro systems that accurately reflect the in vivo process under investigation. Establish and refine genetically based • There is no comprehensive tumor model systems that can faithfully registry, tumor bank, and familial recapitulate the complexity, tissue bank. It is especially important heterogeneity, and diversity of human that these be comprehensive and brain tumors. organized on a national level, given the rarity and heterogeneity of the most informative tumors and familial situations.

Cancer Genetics and Epidemiology 35 RESOURCES NEEDED both the organism and cell culture levels. Particularly relevant is the need • There is a strong need for organized to fortify efforts for the development and coordinated brain tumor registries, and refinement of mouse models of including family histories and human brain tumors harboring extensive clinical and pathological commonly occurring genetic lesions. information. These registries should be Such cancer-prone models will find coupled with tumor samples that are great utility in the identification of equally well characterized and with pathways and their interactions, as well somatic noncancerous tissues from as for loci that modify the effects of affected individuals and their family these pathways. Significant emphasis members. It would be particularly should be placed on the development useful if such centralized resources and design of mouse models that maintained strong technical support to enable assessment of the role of genes conduct routine genome-wide studies, in both tumor initiation and tumor including expression profiling, in situ maintenance. hybridization of tissue arrays, and • The interdisciplinary nature of high-density genotyping and mutation neurooncology makes it essential to analysis. Centralization of these augment the opportunities for technical efforts would provide for physicians to receive training in efficient and thorough utilization of molecular oncology and developmental these precious samples and enable neurobiology. It is equally essential for investigators to obtain such basic scientist trainees to receive information without the need to build training that is medically relevant to or develop advanced capabilities molecular neurobiology. Similarly, themselves. there exists a need for programmatic • It would be widely useful to establish a funding mechanisms that can form a compendium of gene expression bridge between the activities of patterns and genome-wide genotypes established investigators from different of tumors of many different histologies disciplines focused on common themes to be used for correlative studies with in neurooncology. The design of the regard to cell type, developmental peer review of such grants should stage, and their response to therapeutic consider the special needs and agents. The Brain Tumor Genome circumstances of such interdisciplinary Anatomy Project BT-GAP and the efforts. Finally, the relative paucity of Cancer Genome Anatomy Project understanding of this dread disease (CGAP) are making significant underscores the desirability to develop progress with regard to human tumors, rapid funding mechanisms but the genome infrastructure to emphasizing novel and, perhaps, analyze mice lags far behind. This is a preliminary ideas (cf. Department of serious problem in that it hampers the Defense “concept grants”). 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

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 Edward A. Neuwelt Fred Hochberg William M. Pardridge Kenneth A. Krohn Bruce R. Rosen Kathleen R. Lamborn Gail Segal Sarah J. Nelson Arthur W. Toga

STATEMENT OF THE PROBLEM being developed to use such strategies to examine gene expression, a strategy that will The past 60 years have seen a progression in improve detection, staging, treatment the field of imaging from the early use of selection, treatment monitoring, and cerebral angiography and prognosis. Imaging techniques are also now pneumoencephalography to the development being linked to surgical and radiation of early radionuclide techniques and the therapies. Pre- and intraoperative imaging advent of X-ray computed tomography (CT) methods using CT, MRI, PET, and SPECT, in the 1970s. The current era has seen the as well as intraoperative methods such as implementation of magnetic resonance radioisotope probes, optical imaging, and imaging (MRI) in all its permutations intraoperative MRI, are all finding a place in (structural, functional [fMRI], perfusion, planning surgical or radiation therapy for diffusion, and spectroscopy), single-photon patients and in sampling or targeting tissue emission computed tomography (SPECT), for biopsy. These technologies also have a positron emission tomography (PET), and role in avoiding critical brain areas when intraoperative ultrasound. These techniques, destructive lesions or surgical resections are now part of the clinical mainstream, are used planned. They may also be important in individually or in combination to better evaluating the plasticity of normal brain understand the basic mechanisms, tissue after such procedures, either during pathophysiology, and clinical features of development in pediatric brain tumors or in brain tumors and their responses to therapy. adults. They are also used to make therapy safer and more accurate, ultimately improving the The development of cellular- and molecular- quality and duration of life for patients. based imaging will provide many new opportunities to assess brain tumors at a Functional imaging—the visualization of molecular level in animal and clinical physiologic, cellular, or molecular processes models, as well as the ability to monitor in living tissue—now provides insights into gene therapy. As imaging techniques tumor blood flow, glucose or oxygen continue to evolve, it will be possible to metabolism, and many other hemodynamic, visualize and quantitate changes as cells physiologic, and biochemical processes. transform from normal to precancerous to Such approaches may provide a means to cancerous. It may one day be possible to identify molecular structures or receptors evaluate at-risk patients earlier in cancer that cover the surface of a tumor and to help pathogenesis, perhaps before a tumor predict its natural history and response to becomes malignant. It is anticipated that, certain treatments. Attempts are already with the information obtained from the use

Imaging 37 of such imaging techniques, it will be metabolic pathways and specific cell cycle possible to visualize the actual molecular functions that become altered in cancer. signatures of cancer in vivo. The ability to detect fundamental changes associated with It is also clear that better use can be made of a tumor cell will thus vastly improve our existing data derived from imaging ability to detect and stage tumors, select techniques. Combining in vivo phenotypic appropriate treatments, monitor the information about tumor characteristics with effectiveness of a treatment, and determine ex vivo analysis at genetic, cellular, and prognosis. chemical levels can provide better correlations among these variables and the For example, patients may be selected for a patterns seen in images obtained in vivo. particular drug therapy on the basis of Four-dimensional (spatial and temporal) imaging before drug administration. A data analysis of these characteristics should drug’s effect on specific protein interactions, provide new insights into the natural history signal transduction, or metabolic pathways of tumor growth, patterns of spread, and could be measured, thereby providing new responses to therapy. When optimized into endpoints for monitoring drug response. In probabilistic data structures that account for all probability, nomograms of response variance, not only in normal brain structure could be created for populations receiving but also in tumor behavior, these approaches therapies. Clinicians would benefit from should provide new and useful tools for quantitative methods for the identification of optimizing clinical trials. Image analysis “partial response” and “complete response.” techniques that integrate information across These would serve as endpoints to replace modalities, spatial and temporal scales, survival in clinical trials. subjects, trials, and species will require the development of new algorithms; an In imaging, as elsewhere in cancer research, emphasis on neuroinformatics for the animal models of cancer are making it incorporation of images into clinical trial possible to perform certain kinds of studies databases; and the incorporation of genetic, that are difficult, if not impossible, to demographic, and clinical data sets. perform in humans because of practical or ethical considerations. A distinct advantage CHALLENGES AND QUESTIONS of noninvasive imaging in animal models of cancer is the ability to perform repetitive, The goals of the National Cancer Institute’s noninvasive observations of the biologic plan for Fiscal Year 2001 with regard to processes underlying cancer growth and imaging are quite appropriate to the development without sacrificing the animal. challenges associated with imaging brain The development of small-animal imaging tumors. These goals include the following: devices, which can produce serial images of experimental brain tumors in small animals • Develop and validate imaging and incorporate all of the functional technologies, probes, and radiocontrast strategies just described, should provide a agents that have the sensitivity to powerful new tool for experimental studies detect precancerous abnormalities and of brain tumor behavior and response to very small cancers. treatments. Further development of targeted • Develop imaging techniques that contrast agents, ligands, and imaging probes identify the biological properties of also need to be supported because they will precancerous or cancerous cells that provide better in vivo elucidation of the key will predict clinical course and response to interventions.

38 Report of the Brain Tumor Progress Review Group • Develop minimally invasive imaging Image Outcome and Monitoring technologies that can be used in Interventions interventions and assessment of treatment outcomes. Imaging has a role in monitoring both • Foster interactions and collaboration treatment progress and outcomes in addition among imaging scientists and basic to drug toxicity. Available radiographic biologists, chemists, and physicists to endpoints are inadequate as treatment help advance imaging research. markers and endpoints. Efforts must be • Create infrastructure to advance made to achieve realistic criteria (“cut research in developing, assessing, and points”) for partial and complete response to validating new imaging tools, therapy and to define criteria for assessing techniques, and assessment toxicity to white matter, cortex, and methodologies. ventricular structures. In the case of treatment, there are several aspects under Each of the goals listed above is associated consideration, each with its own challenges. with a set of challenges and questions. The Drug effectiveness should be assessed major challenge for the imaging community within the context of tissue concentration is to accurately measure tumor burden and (labeled drugs, etc.), drug delivery of small function (phenotype). This goal will be versus large molecules (i.e., blood-brain pursued by using different imaging barrier, blood-tumor barrier), and biological technologies, probes, and paradigms (see effect (function) of the tumor. Exhibit 1) in order to better characterize brain tumors before, during, and after Image-guided strategies include the treatment. A further challenge will be following: validation of the new imaging paradigms through animal experiments, in vivo versus • Preoperative and intraoperative ex vivo (molecular) analysis, and clinical planning (e.g., image-guided correlations. stereotactic biopsy and resection using PET, MR, fMRI, magnetic resonance One goal of surrogate marker imaging is spectroscopy [MRS], and optical differentiating the cellular and molecular intrinsic signal [OIS] imaging) characteristics of tumor from those of • Radiation therapy (e.g., image-guided normal brain tissue. Another goal is to stereotactic radiosurgery using PET, image the biology (molecular biology) of MR, fMRI, MRS, and OIS) brain tumors with new techniques and • Development of multimodal image probes. A final goal is to arrive at non-lethal registration (e.g., MR, fMRI, MRS, endpoints for the assessment of treatment OIS, and PET) and the natural course of tumor growth. This • Development and availability of can be done with the development of four- improved instrumentation (e.g., high- dimensional nomograms specific for tumor field human MR systems) and hybrid and age of patient and with spatial-temporal imaging devices (e.g., combined CT- measurements, using a multimodality, PET or MRI-PET tomographs) multispectral approach. 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 archiving, and integrating information across received little attention in the past, and little all data types. Databases provided for these is known regarding the mechanism (e.g., clinical trials must contain real-time imaging demyelination, axonopathy, edema) of this displays as well as quantitative data (e.g., toxicity and its temporal course. Toxicity volume, spectral ratios, diffusion ratios, and can also be gauged by imaging the normalized cerebral blood flow [CBF] and vasculature of normal brain and tumor. volume [CBV] information). The field of Similarly, toxicity indices can be created for informatics is growing rapidly in the gray matter function and plasticity in treated biological sciences and can make a major children. impact in the area of brain tumor research. Unlike other organs in the body, the brain Transgene and Molecular-Based has a distinct and important architecture. Therapies Both the type and location of brain tumors are therefore important in understanding Imaging at the molecular level (assuming a their causes, growth patterns, and response homogeneous region of interest) is on the to therapy. horizon. The task will be to generate reporter gene constructs that can be imaged A logical framework for integrating as markers for transgene delivery (e.g., viral information about these lesions would be to vectors) and for markers of change in use the anatomical structure of the brain specific protein interactions, signal itself as the framework for an transduction, or metabolic pathways. These atlas that would store information about all protein interactions and the specific steps in patients, whether studied in scientific signaling pathways can be targeted by protocols or undergoing conventional specific anti-tumor drugs, and drug efficacy clinical treatments. Imaging can provide this assessments can be made by noninvasive architecture for databases and atlases. It will imaging of the specific pathway. In the be important to develop the tools and future, patients may be selected for therapy informatics methods to integrate imaging on the basis of imaging before drug studies across modalities, spatial-temporal administration. Response could be scales, subjects, trials, and species. Such monitored by measuring changes in specific databases and atlases should be four- protein interactions, signal transduction, or dimensional (three in space and one in time, metabolic pathways. In this way, new where the latter variable can be the age of endpoints for monitoring drug response the subject as well as the time course of could be developed. tumor growth and treatment). Because brain anatomy is highly variable among Development of Databases, Informatics, individuals in a population, it is also Standards, and Software Tools advisable that such atlases be probabilistic in nature, thereby providing distribution The NCI has created brain tumor study estimates for the locations of regions and groups offering Phase I and II studies that tumors. These four-dimensional, provide the basis for intergroup Phase III probabilistic, image-based databases can be trials. Examples include the nationwide linked to other data sets, including clinical, approaches to brain lymphoma and molecular, histological, and therapeutic oligodendroglioma. It is important to variables. translate the above-described imaging advances to serve clinical trials. Systems To accomplish such an endeavor, it will be must be provided for sharing, accessing, important to develop tools to normalize

40 Report of the Brain Tumor Progress Review Group image acquisition across sites and to develop monitoring interventions in patients with a standardized core image analysis and brain tumors. feature-extraction pipeline for the quantitative processing of imaging studies Priority 3: from all modalities. For example, a nationwide trial for the therapy of brain Develop databases, standards, and lymphoma in 600 patients can provide software tools that integrate seminal data on the rate of response, demographic, clinical, and imaging relationship between drug dose and information in a form that can be used to volumetric diminution of tumor, changes in identify characteristics that are critical spectra of magnetic resonance, and diffusion for managing brain tumors and tailoring parameters. The clinical trials format is the therapy to individual patients. ideal mechanism by which reliance on individual data sets can be replaced while RESOURCES NEEDED providing integration across laboratories and experimental trials. This important, final Resources needed to address these recommendation is critical and, based on challenges include the following: experiences in other fields, will require appropriate funding to provide the force for • Continuation and expansion of the data integration. It will be necessary to imaging research programs described create data standards (e.g., voxel size, in Exhibit II diffusion weighted imaging (DWI) software • Development of a “shared” and sharing) and communication pathways and “accepted” informatics and database brain atlases at nationwide meetings. infrastructure • Meetings to facilitate relations among RESEARCH AND SCIENTIFIC industry, academics, regulatory, and PRIORITIES funding agents • Research and training funds to support The following research priorities were the scientific priorities 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

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: 1. There is an apparent clinical A. Surrogate markers: need for functional cognitive 1. Methods need to be studies. Because other developed for choosing sessions, especially the among many options; for Radiation Therapy session, example, using MRI alone, identified the same need, this one can assess tumor volume, call should be heeded. hemodynamics (CBF, CBV, 2. fMRI can be combined with BBB permeability), tissue anatomical, biological, and water diffusion, and blood functional assessment of 31 O2, as well as proton and P- white matter changes. MRS. At present, it is fMRI/DWI tomography impossible to perform all would be one priority, and these imaging the other imaging modalities motifs/measurements well, described below would also and there is little be involved. standardization of techniques 3. Assessment of vascular across sites. toxicity/BBBs in this 2. An overall concern is how to category will overlap with pick and choose among the surrogate markers, especially different MRI motifs (let for anti-angiogenic alone nuclear, CT, and other treatments. Hemodynamics is imaging techniques), select a near-term goal for MRI. targets for validation, and compare studies by using the C. Imaging Therapeutic Effect: different imaging methods in 1. It is difficult to precisely the study of different patient define the need for groups with different quantitative in vivo endpoints. pharmacodynamics within 3. Priorities and challenges the tumor. This issue seems might include both largely relegated to nuclear technology development imaging, but MRS is likely to (needed to facilitate improved play some role as well. The quantification, especially for area of pharmacodynamics MRS and fMRI) and basic represents an opportunity for clinical validation studies industrial collaboration (e.g., (although the challenge above by major pharmaceutical holds true here). corporations) in a national 4. Ways need to be found to to effort to radiolabel all standardize acquisition across prospective therapeutic drugs. multicenter trials with 2. Gene expression presents a industrial collaboration. “grand challenge.” MRI/MRS

44 Report of the Brain Tumor Progress Review Group is likely to play an important (NMR) spectroscopy of role in this new field of excised tissue “molecular imaging”; it has 4. Educating radiologists and the right elements and will be oncologists concerning the developed further in the most appropriate applications decade ahead. of the technology and the interpretation of the II. MRS has been a tool for examining the biological significance of alterations in cellular metabolites associated clinical MRS data with carcinogenesis and treatment response in animal and cell systems for more than 20 B. Single-voxel proton MRS techniques years. Recent developments in technology can only interrogate regions that are have allowed MRS to be increasingly thought to be suspicious from routinely applied to patients with brain morphological or other physiological tumors in research and clinical studies. criteria. Proton MRSI can be used to map out spatial heterogeneity in both There are three major areas for the lesion and surrounding tissue for development: studies in animal tumor models and patients. Applications include directing A. Single voxel water suppressed tissue biopsies, planning surgical proton MRS is the most widely resection or other focal therapies, available MRS technique for clinical defining the extent of disease, and applications. It has been shown to evaluating response to therapy. assist in characterizing tumor type and Challenges to this technology are as grade, distinguishing tumor from other follows: mass lesions, and determining whether 1. The need for improved data changes in lesion morphology acquisition techniques for correspond to tumor recurrence or optimized shimming, more treatment-induced necrosis. Challenges robust water and lipid to this technology include the suppression, more accurately following: tailoring the excitation to the region of interest, and 1. Choosing the most improving signal-to-noise appropriate region of the ratio by using either higher lesion to study field magnets or more 2. Developing databases of in sensitive, custom-designed vivo spectral characteristics radiofrequency coils and using pattern recognition 2. Developing post-processing techniques to identify methods for displaying fingerprints that are imaging and spectral data, predictive of histology registering serial data from 3. Validating the in vivo follow-up examinations, and findings by correlating them deriving quantitative indices with results obtained by ex describing the metabolic vivo analysis of molecular changes within the lesion and markers, histology, and surrounding normal tissue nuclear magnetic resonance that can be used for treatment

Imaging 45 plannig and assessing high-resolution, high-precision CBF and response to therapy vascular permeability imaging will be most 3. Validation of the technology amenable for assessment of anti-angiogenic as a tool for routine clinical therapies. It is possible, perhaps likely, that evaluation of brain tumor it will be useful for evaluating a wide variety patients in both single and of novel therapies. For these reasons, it is multi-institutional settings prudent to encourage explorations in the use of this technology in the evaluation of brain C. Multi-nuclear MRS: At present, the tumors. applications of 31P, 13C, and 19F MRS are limited by low sensitivity and IV. Nuclear (PET, SPECT, gamma mainly involve cell and animal model camera; special topics that require further systems. In cases where specific drug development) therapies have a signature that can be detected using one of these A. Cell proliferation (assessment within 5 methodologies, there is promise for years) noninvasive monitoring of drug 1. Established probe: 11C-TdR delivery and function. More generally, 2. Developing probes: 18F- it is possible to measure pH, cellular 3’FLT, 124I-IUdR, 76Br- bioenergetics, and phospholipid FbrAU metabolism. Challenges for this technology include the following: B. Angiogenesis (validation of assays for 1. Obtaining 13C-labeled drugs monitoring anti-angiogenesis therapy, at a price that is economic for assessment within 5 years) routine basic and clinical 1. Blood flow (15O-water, 99mTc- research studies sestamibi, 201Tl-thallium, 2. Availability of high field 133Xe-saline, etc.) human MRI scanners in order 2. Blood volume (15O- or 11C- to obtain in vivo 13C, 19F, and carbon monoxide–labeled 31P data at adequate signal-to- erythrocytes [RBCs], or noise and spatial resolution 99mTc-RBCs) 3. Capillary permeability (82Rb- III. Recent developments in CT merit its rubidium, 68Ga-DTPA, 68Ga- consideration as a relatively inexpensive and transferrin, 18F-, 123I-, 131I-, widely available method for assessing 124I- or 99mTc- labeled physiological responses to brain tumor albumin) therapy. The development of the helical 4. Oxygen metabolism (15O- scanning technique and, most recently, oxygen) multi-detector technology permits the measurement of CBF at very high spatial C. Hypoxia (assessment within 5–7 years) resolution with high precision and accuracy. 1. Established probe: 18F- This technology is moving rapidly and is fluoromisonidazole likely to become the predominant CT 2. Developing probes: 61Cu- or technique in the course of the next few 64Cu-ATSM, 18F-EF1, 18F- years. This capability and widespread EF5, others availability presents an opportunity for inexpensive and widely available functional imaging of brain tumors. It is expected that

46 Report of the Brain Tumor Progress Review Group D. Transporter up-regulation (assessment H. Molecular imaging specifics within 5–7 years) (assessments over next decade) 1. Amino acid transporters (11C- 1. Endogenous gene expression methionine, 18F-FET, 18F- (transcriptional FACBC, etc.) activation/depression) 2. Nucleoside transporters (11C- 2. Post-transcriptional FMAU, etc.) modulation/stabilization of 3. Choline transporter (18F- mRNA fluorocholine) 3. Protein-protein interactions 4. Glucose transporter (11C- of specific steps in selected 3OMG, 18F-FDG) signal transduction pathways 5. Other substrates I. Gene therapy (assessments over next E. Cell surface receptors/antigens decade) (endothelial cells and tumor cells; 1. Vector delivery and transgene assessments over next decade) expression (reporter 1. Transferrin receptor (67Ga- transgene imaging transferrin, 111In-DTPA established) transferrin chelate, etc.) 2. Trafficking and targeting of 2. EGF receptor (radiolabeled genetically modified T cells antibody or peptide) 3. Benzodiazepine receptor V. Optical intrinsic signal (OIS) imaging: (iodinated-PK11195) 4. Other cell surface A. The development of more rapid, receptors/antigens (e.g., Flt1 sensitive, and efficient optical and Flk1/KDR receptors for instrumentation with multispectral VEGF) capabilities, in order to observe the etiology of various functionally active F. Cell matrix antigens (assessments cell types in normal and pathogenic over next decade) tissues 1. Integrins (RGD- and other radiolabeled peptides B. Imaging systems compatible with interoperative MR environments G. Molecular imaging strategies/issues (assessments over next decade) C. The ability to examine molecular 1. Reporter gene imaging concomitant to intraoperative optical (indirect assay; principle measurements using probes and other established) markers 2. Enzymatic amplification vs. receptor binding and D. Compatibility between other internalization intraoperative instrumentation and 3. Oligonucleotide/aptamer optical acquisition and display, such as (direct binding/assay of microscopes, stereotactic localizers, mRNA/proteins; to be etc. established) 4. Probe/contrast agent delivery E. Co-localization of multimodality issues (small molecules vs. displays, including optical, pre- and macromolecules)

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 validating new imaging tools, techniques, Cancer: The Goals and assessment methodologies.

Over the past several years, the National The NCI has already made significant Cancer Institute (NCI) has been keenly progress in the past several years toward aware of the potential power of imaging reaching these goals with the introduction of techniques and molecular imaging in various programs and initiatives: particular. The Biomedical Imaging Program (BIP) (http://cancer.gov/bip/default.htm) • NCI has awarded three grants to of the Division of Cancer Treatment and support In-Vivo Cellular and Molecular Diagnosis is responsible for the extramural Imaging Centers (ICMIC) grant portfolio and programs related to (http://grants.nih.gov/grants/guide/rfa- oncologic imaging. Imaging has been files/RFA-CA-99-004.html). The ICMIC identified as an area of “Extraordinary grants will facilitate interaction among Opportunity” in the past several “NCI scientists from a variety of fields to conduct Bypass Budgets” multidisciplinary research on cellular and (http://2001.cancer.gov/imaging.htm). The molecular imaging. The integration of this NCI Bypass Budget breadth of expertise is still in its early stages. (http://2001.cancer.gov/2001.htm) is a public document produced annually by NCI • The NCI has also funded nine pre- to identify for the Administration and ICMIC planning grants Congress those scientific priorities on which (http://grants.nih.gov/grants/guide/rfa- the budget appropriation will be spent. The files/RFA-CA-99-002.html) . The pre- imaging-related goals of the NCI include: ICMIC planning grants provide time and i. Develop and validate imaging funds for investigators and institutions to technologies and agents (e.g., probes, prepare themselves, organizationally and radiocontrast agents) that have the scientifically, to establish an ICMIC sensitivity to detect precancerous • Small animal models, particularly abnormalities or very small cancers. genetically engineered mice, are powerful ii. Develop imaging techniques that discovery tools, but we have yet to capitalize identify the biological properties of fully on their potential in cancer research. precancerous or cancerous cells that will NCI has funded five Small Animal Imaging predict clinical course and response to Resource Programs (SAIRP) interventions. (http://grants.nih.gov/grants/guide/rfa- iii. Develop minimally invasive imaging files/RFA-CA-98-023.html). This initiative technologies that can be used in supports activities to develop and apply a interventions and in assessing treatment wide variety of imaging modalities that outcomes. focus on functional, quantitative imaging. iv. Foster interaction and collaboration Quantitating image data for small animals among imaging scientists and basic will lead the way to quantitative methods biologists, chemists, and physicists to help that can be applied in humans. An additional advance imaging research. five SAIRPs will be funded in fiscal year v. Create infrastructures to advance 2001. research in developing, assessing, and

Imaging 49 • New drug discovery programs are perform clinical feasibility tests of producing an increasing number of instruments able to visualize epithelial tissue molecules for investigation, in turn at risk for common cancers and recognize stimulating a need for research that the optical signatures of precancerous integrates imaging techniques into abnormalities. This often involves preclinical and clinical studies to assess molecularly oriented techniques. newly developed therapeutic agents. NCI has set aside funding for the development 2. Develop, synthesize, validate, and and application of labeled therapeutic agents distribute to the research community novel as compounds for imaging studies and imaging agents. imaging agents that serve as metabolic • Expand a program similar to NCI’s markers of response to newly developed Rapid Access to Intervention Development therapeutic agents. The Development of (RAID) initiative (which is designed to Clinical Imaging Drugs and Enhancers accelerate the movement of novel (DCIDE)(http://cancer.gov/bip/dcide.htm) interventions from the laboratory to the program will facilitate the development of clinic) specifically for imaging agent novel imaging agents in preclinical development. The Development of Clinical development. A detailed overview of the Imaging Drugs and Enhancers (DCIDE) newly approved DCIDE program will be program (http://cancer.gov/bip/dcide.htm) presented at a future date in Academic will facilitate and promote preclinical Radiology. development and validation of important imaging agents and ligands. NCI will, on a Cellular and Molecular Imaging in competitive basis, synthesize, test, and Cancer: Meeting the Goals distribute probes that image the physiological and functional status of tumor To ensure that the initially defined goals for tissue in the human body. The DCIDE cellular and molecular imaging are met and program will be described in detail in a completed in future years, the NCI has set future issue of Academic Radiology. forth in the 2001 Bypass Budget specific • Establish a publicly available priorities and initiatives. These include: database of agents available to the research community, together with information on 1. Accelerate development of clinically their properties. useful technologies for detecting malignant and precancerous cells and for visualizing 3. Expand and improve clinical studies of their functional characteristics. molecularly based imaging modalities and • Expand the number of In-Vivo image-guided interventions. Cellular and Molecular Imaging Centers (ICMIC) in 2001, 2003, and 2004. 4. Integrate molecular and functional • Expand the Small Animal Imaging imaging technologies into drug development Resources Program (SAIRP) to improve and early clinical trials access to researchers testing new approaches (http://cancer.gov/bip/concepts.htm - c4). to diagnosis, treatment, and prevention in • Support the development of in-vivo animal models of cancer. NCI will foster and molecular clinical imaging research collaborations between this program and the tools for assessing the biological effect of Mouse Models of Human Cancers cancer drugs on their intended target or Consortium (MMHCC). pathway. • Support multidisciplinary centers of • With this continued investment in expertise to develop optical technologies and the future of imaging research, it will soon

50 Report of the Brain Tumor Progress Review Group be possible to apply the techniques databases in which such complex and large- developed to image novel molecular targets, scale data sets (from patient outcomes to specific genetic pathways, signal gene chip arrays) can be organized, archived, transduction, cell cycle alterations, accessed, and distributed. Funding agencies angiogenesis, apoptosis, and numerous other should also provide opportunities for biologically relevant processes known to investigators to meet across disciplines to occur in cancer in routine clinical practice. develop standards for communicating such information and to alter the sociological Cellular and Molecular Imaging in outlook of investigators from one of Cancer: The State of the Art isolation and territoriality to integration and sharing. Finally, specific emphasis should be It is likely that the NCI goals and visions of placed on funding programs that develop cellular and molecular imaging in cancer tools to standardize and normalize image research and patient care will be met. It is acquisition across investigational sites and gratifying to note that the power of imaging to develop core, quantitative analysis and with PET, nuclear medicine techniques, feature extraction algorithms for the post- MRS, ultrasound, CT, optical imaging, and processing and distribution of imaging other techniques is being recognized and studies acquired from all imaging modalities these techniques are becoming available in in patients with brain tumors. 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, spatial- temporal domains, subjects, trials and species. This will require appropriate funding for the development of atlases and

Imaging 51 Tumor Immunology Co-Chairs: Darell D. Bigner, M.D., Ph.D., and Richard M. Ransohoff, M.D.

Participants: David Ashley Linda M. Liau Diane Traynor E. Antonio Chiocca Sherie Morrison Carol Wikstrand Glenn Dranoff David Parkinson Han Ying Carol Krutchko Sam D. Rabkin Richard Youle Andreas Kurtz Tom Rozman Jeanne Young Lois Lampson John H. Sampson John S. Yu

STATEMENT OF THE PROBLEM CHALLENGES AND QUESTIONS

There is a current lack of basic information The areas in which further information concerning the functioning of the immune would be most beneficial include the system within the central nervous system following: (CNS). It is imperative to narrow this sizeable gap in understanding of the • Identifying the antigen-presenting interaction of these two systems in order to cell(s) (APC) of the CNS: For gain insight into the pathogenesis of primary example, is there a CNS APC, or must brain tumors and the immunotherapeutic we use APCs such as peripheral approaches that are most likely to produce immune system dendritic cells? successful outcomes in their treatment. • Determining the extent and pattern of the lymphoid drainage pathways of the For broad purposes of discussion in this CNS: Evidence for lymphoid drainage report, tumor immunotherapy may be pathways in the CNS has been found in considered to be both cell mediated (T- animals, but little is known of their lymphocyte cell) and antibody mediated. existence or characteristics in humans. Both types of immunotherapy are • Elucidating the mechanisms or characterized by great specificity and low pathways by which marrow-derived toxicity, as long as they are carefully immunocompetent cells traffic to the administered. Current T-cell strategies CNS: Chemokines, which are involve recruiting tumor-reactive T-cells important in this process, are produced after exposure of autologous professional by resident neural cells, including antigen-presenting cells to tumor antigens, glioma cells, and are essential for and reinfusing them. Tumor-specific leukocyte recruitment to the normal antibodies or their smaller fragments, such and inflamed CNS. Chemokines also as single-fragment chains, are generated by provide growth regulatory signals for hybrid technology from conventional or glia during development and neoplasia double-knockout/double-transgenic mice or and thus may play a complex role in from phage display systems. Antibodies may the response of the CNS host organ to kill tumor cells in “unarmed” fashion or by tumor. directing drugs, radionuclides, or toxins to • Identifying the important immune tumor cells. 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 disorders of the CNS would also be CNS tumors that also have advantageous for the examination of encephalitogenic potential: Powerful immunologic effector mechanisms. immune responses underlie the relatively rare paraneoplastic Another barrier to optimal progress in tumor syndromes, and immunotherapy targets immunology is the lack of methodological potentially exist inside the CNS. consistency. Different immunotherapy However, unless directed groups use differing immunization appropriately, antigenic therapy bears strategies, thus diminishing the ability of the risk of extensive CNS destruction. clinicians to reach significant conclusions by • Further understanding of the comparing their results across trials. For mechanisms by which CNS tissues and example, at least four institutions are CNS tumors exert both local and currently involved in dendritic cell trials, but systemic immunosuppressive effects: each group uses a different method of cell Although brain tumor–related preparation. Another area in which immunosuppression is not severe establishing a consistent methodology would enough to cause opportunistic be beneficial is the key investigative infections, these effects may interfere analyses of the immune responses of patients with cell- and antibody-mediated involved in clinical trials. Finally, although tumor immune mechanisms. generation of CTL responses is not generally considered a gold standard for therapeutic BARRIERS success, it is an important technical outcome measure and should be determined in similar The development of predictive large and fashion by all investigators. Such is currently small animal models of primary CNS tumors not the case. is of great importance in the application of immunotherapy to primary brain tumors. There is a strongly felt need among Animal models have yielded disconcertingly immunotherapists that some outcome little cross-species applicability in the measures short of survival would be treatment of brain tumors in the past; for advantageous in evaluating investigative example, the pharmaceuticals that have been therapies rapidly and efficiently. Possible found to be effective in mice with outcome measures could involve well- experimental allergic encephalomyelitis, a defined immunological endpoints and murine model of multiple sclerosis, have not determination of toxicity or demonstration proven effective in human trials. There are that the desired immune response has indeed currently no predictive animal models for been elicited. immunotherapy. However, the development of genetically modified mice provides An additional barrier to obtaining the promise of the ability to extrapolate the maximal benefit from clinical trials of findings of mouse studies more effectively immunotherapy has been the lack of an to human applications. optimal data set from all patients entered in those trials. For example, stratification for In mice, such models could be used to the degree of pre-treatment immunological address critical problems, including the suppression is not always done. It has been effector mechanisms by which immune suggested that future initiatives should responses to tumors can eliminate neoplastic include, for instance, a complete proteomic cells. The creation of animal models of the analysis of the components of acid-washed paraneoplastic, immunologically mediated membrane preparations used to pulse

Tumor Immunology 53 dendritic cells, and ultimately molecular Priority 2: knowledge of each antigen employed. Characterize both CNS and systemic A common theme of the preceding immune responses in patients with brain paragraphs, following but by no means tumors. eclipsing the discussion of animal models, is the need for consistency: in immunization Protective (tumor-destructive) responses are strategies, in a consensus on the use of poorly understood. Deleterious reactions are outcome models short of survival, and in frequently generated by interactions between obtaining the most complete and clinically- neoplastic cells and the immune system informative data set possible from patients response apparatus. These interactions are in clinical trials. capable of generating tumor growth factors, angiogenic factors, and immunosuppressive RESEARCH AND SCIENTIFIC components. PRIORITIES Tumor-associated immunosuppression is little understood, yet clinicians must learn to Among the areas of tumor immunology control this mechanism and develop means considered to be of greatest value and of dealing with it. Helpful investigatory interest in the development of brain tumor areas would include characterization of the immunotherapy, the following topics were underlying mechanisms, implications for the selected by a consensus of the PRG natural history of the tumor, and participants as most deserving of research consequences of the immunosuppressive focus and funding: reaction for the immunotherapy of the tumor. Priority 1: Priority 3: Develop techniques of antigen identification, resulting in a readily Consider the problems and challenges accessible source of information on the posed by patient and tumor genes and gene products that produce heterogeneity. antigens. Individual patients are heterogeneous, for A preliminary database already exists both genetic (e.g., human leukocyte antigen) containing information characterizing genes and epigenetic reasons, in their abilities to that are differentially expressed in tumor respond to immunotherapy. Tumors are cells as opposed to those typically found in heterogeneous with regard to antigen non-neoplastic tissue. expression. Heterogeneity needs to be understood in each tumor so that as many as • To accomplish antigen identification, three or four individual molecular antigenic researchers will require high- species may be targeted at one time. Target throughput screens to define the cells also display heterogeneity with regard antigens recognizable by T-cells. to intracellular components that confer • Similarly, high-throughput screens are susceptibility to enzyme- or Fas-mediated needed to permit the identification of programmed cell death. cell surface antigens and antigens located in the extracellular matrix, which may be approachable by antibody-targeted therapy.

54 Report of the Brain Tumor Progress Review Group RESOURCES NEEDED transgenic mice with murine immunoglobulin genes replaced with • Brain Tumor Clinical Consortia for human immunoglobulin genes. Such expediting chemotherapy and radiation mice can be used for production of therapy are funded by the National fully human monoclonal antibodies for Cancer Institute (NCI) and are repetitive administration to patients productive. Similar clinical consortia with brain tumors and other cancers. for immunotherapy, especially for • Clinical trial support mechanisms are Phase I and II trials, are needed to needed to cover the cost of research expedite and standardize approaches. activities, including immunological There are enough institutions (five or assays, scanning, and autopsies, not six) ready to form the critical mass covered by third-party payers. The necessary for such consortia. Human National Institute on Aging trials are more important than animal successfully worked with investigators studies. For example, cytokines are and advocates in dementia to obtain species specific, and human cytokines funding for research autopsies. can be evaluated only in primate Advocates should encourage federal systems. legislation to provide a payment • Dedicated support from the National mechanism for research autopsies. Institute of Neurological Disorders and • Accessible proteomic facilities are Stroke (NINDS) to understand basic needed to provide molecular mechanisms of immune responses in characterization of antigens now the CNS is important for demyelinating presented in unpurified, crude form, and viral diseases as well as for brain such as cell lysates. 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/double-

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 Andreas Kurtz Michael Berens Linda M. Liau Tom Curran Luis Parada Ronald A. DePinho David H. Rowitch Glenn Dranoff Evan Snyder Henry Friedman Carol Wikstrand Mark A. Israel

STATEMENT OF THE PROBLEM community needs better cell culture and tissue models that more accurately Models are central to making the transition reflect the biology of brain tumors. from scientific concepts to understanding the • Traditional rodent models do not reality of a tumor in a person. They may be accurately reflect the growth, invasion, used for therapeutic screens, in preclinical histology, gene expression profiling, trials, or to study the basic biology of vasculature, and stromal interactions of tumors. Unfortunately, the available model various intracranial tumors. systems, whether at the cellular, tissue, or • No genetically defined brain tumor animal level, do not accurately represent the models exist in species other than in biology of human brain tumors. Established laboratory mice. Such animal models glioma cell lines develop multiple genetic may offer additional insights into the changes over time, so that they no longer biology of specific brain tumor types or reflect the biology of the tumor in the may allow the testing of specific person. In addition, current primary tissue therapeutic modalities that is not models cannot be maintained in a healthy possible in mice. condition for more than a few days. Finally, implantation animal models do not reflect Future Models the interaction between tumor and host that occurs in the human. • The gene expression profiles, controlling elements, pathways, and CHALLENGES AND QUESTIONS cells of origin for brain tumors remain largely unknown. Existing Models • Molecular reagents, such as tissue- specific promoters and enhancers, to • Conventionally used glioma-derived create genetically accurate models of cell lines contain genetic and gene brain tumors are lacking. Further, it is expression alterations that are ill necessary to identify to oncogenes and defined and do not necessarily reflect tumor suppressors, as well as to the primary tumors from which they develop the technology needed to were derived. Therefore, data derived combine alterations in the appropriate from them may not reflect the biology, cell types. heterogeneity, or therapeutic response • There are no adequate mechanisms to of the primary tumors. The scientific correlate genetic alterations in mouse

56 Report of the Brain Tumor Progress Review Group tumors with their proposed human The development of accurate mouse models counterparts. is very important. In addition, the • There are no readily available and development of genetically defined brain affordable noninvasive techniques to tumor models in other species should be allow investigators to measure changes encouraged. Such species may include in tumor volume, growth pattern, gene smaller animals, such as Drosophila or fish, expression, and other biological as well as larger animals, such as pigs and parameters of interest. dogs. These have the potential to be used to further understanding of the biology of the Model Availability disease. In particular, the anatomical spatial dimensions of larger animal models may • Investigators who are not directly better allow for the testing of surgical involved in the production of animal interventions and novel delivery techniques. models lack easy and affordable access to these models. Priority 3:

RESEARCH AND SCIENTIFIC Generate methods to validate, compare, PRIORITIES and contrast the animal model with its proposed human counterpart. Priority 1: These methods should include standard Develop tissue and cell culture systems methods such as histology, magnetic that replicate the biology of human brain resonance imaging, anatomical imaging, and tumors more adequately than do the therapeutic response, as well as gene currently available immortalized cell expression and genomic profiling. This will lines. require the development of mouse arrays from the mouse counterparts to the human Specifically, there is a need to develop and BTGAP sequences. In addition, validate primary tissue culture systems such methodologies such as BAC arrays or SKY as spheroids, brain slice cultures, primary analysis will be required to assess the cell cultures, and genetically defined acquired genomic alterations. Adequate immortalized cells, including stem cells. bioinformatics support will be required in These systems need to be characterized as to order to analyze these data. their similarity to the brain tumors that they are designed to model. Further development and use of noninvasive technology is necessary to measure aspects Priority 2: of tumor biology in these animal models. Specifically, there is a need for image Create genetically accurate animal models analysis of gene expression, vascularity, for brain tumors. tumor size, and invasiveness, and for other noninvasive techniques, such as serum or An essential first step is to define and urine surrogate markers. These may require develop reagents, including tissue-specific the generation of specific, genetically altered promoters and enhancers, as well as to reporter mice. expand our capabilities for readily combining multiple genetic alterations in specific cell types.

Experimental Models for Brain Tumor 57 Priority 4: • Resources need to be allocated for the generation of cDNA microarrays based Improve access to and make available at on the mouse equivalent of the human reasonable cost to investigators: BTGAP sequences. • A mechanism must be created to • The reagents needed to create new ensure affordable access to the reagents animal models of brain tumors and models listed above to • Sophisticated technologies used to investigators. Furthermore, the NCI evaluate and validate those models and NINDS should provide resources • The animal models themselves to establish a consortium of brain tumor modeling laboratories for the Expression cDNA microarray and BAC purpose of testing novel therapies. 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.

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 Sandra Rempel Susan Hockfield Steve Rosenfeld Lois Lampson John H. Sampson Marla B. Luskin Harald Sontheimer Robert H. Miller Richard Vallee Maiken Nedergaard Jeanne Young Jasti S. Rao

STATEMENT OF THE PROBLEM tumor cell dispersal and tumor-CNS interactions. A hallmark of primary neuroectodermal neoplasms is their infiltrative nature. By the • The need to consider how further time most such tumors are diagnosed, cells knowledge of the first two phenomena have spread beyond the neoplasm’s could result in new therapies. identifiable mass and into surrounding tissues. These dispersed cells may contribute RESEARCH AND SCIENTIFIC to tumor recurrence in situations in which PRIORITIES the primary site can be controlled by surgery or other therapies. Rather little is known Priority 1: about the process of this spread. Define the molecular constituents The breakout group on Neurobiology: Cell required for dispersal. Migration and Dispersal discussed the nomenclature used to describe cell Although redundancy in motility-based movement from tumor masses into brain genes may make it problematic to isolate parenchyma. To avoid some implications of specific targets, there is evidence that cell- terms such as migration, invasion, and specific isoforms exist for some of these infiltration, it was agreed to use the word proteins. It would be valuable, therefore, to dispersal to describe the movement of tumor identify and determine the function of gene cells through the central nervous system products that regulate motility in (CNS). neuroectodermal tumors. The molecules include possible tumor- or tumor-type CHALLENGES AND QUESTIONS specific motors and cytoskeletal proteins; small GTPases that regulate interactions • The need to understand brain tumor between external signals and internal dispersal through the CNS cytoskeletal organization; cell surface receptors involved in cell migration, • The need for more information on how including those that may mediate start or tumor cells interact with normal stop signals or maintain cell polarity; cellular constituents of the brain. components of extracellular matrix, Emphasis should be placed on including proteases involved in remodeling developing new models for studying extracellular matrix molecules as cells

Neurobiology: Cell Migration and Dispersal 59 migrate; ion channels that may allow which express a variety of cytokines, attract changes in cell shape or cell volume during lymphocytes into the CNS?) migration; G protein–coupled receptors; and the extracellular matrix molecules produced Emphasis should be placed on examining by both tumor and CNS. tumor-CNS interactions in appropriate in vivo and in vitro tumor models. It is Resources needed: important to design assays that determine the functional consequences of these • Use DNA chip technology to examine interactions and whether the perturbations appropriate tumor cell types, preferably are reversible. Studies that integrate the freshly isolated tumor cells rather than anatomy and physiology of tumor-CNS tumor cell lines. It may be worthwhile interactions should receive highest priority. to search for differences among tumor types that display characteristic and Resources needed: different migratory patterns (e.g., juvenile pilocytic astrocytomas through • New models are needed for studying white matter, oligodendrogliomas tumor cell dispersal and tumor-CNS through white matter and into cortex, interactions and medulloblastomas). The group discussed existing models, • This kind of search should also be including two- and three-dimensional carried out for normal glial and models in vitro and co-culture experiments neuronal progenitors, because little is with tumor and normal brain, but focused on known about the specific molecular using existing models and on developing mechanisms underlying migration and new models in which tumor cells could be because normal and tumor cells studied moving through the normal CNS. probably share many common This could be accomplished in brain slices regulatory mechanisms. or in whole animal models, from which slices could be used to examine tumor cell Priority 2: movements. These would be particularly useful if the models resulted in tumors Examine how tumor cells interact with whose cells disperse through the brain and the brain’s normal cellular constituents. are tagged to be clearly distinguishable from normal cells. It is hoped that such animal Little is known about how tumor cells models would be freely available to interact with normal neurons and glia. investigators interested in tumor cell Several kinds of interactions are worthy of dispersal. investigation, including gap-junction formation between tumors and normal Priority 3: astrocytes, altered potassium or neurotransmitter (glutamate) buffering Determine how we can best use the produced by tumor cells in proximity to knowledge acquired through research neurons, synaptic disruption, interactions described in the priorities above to define between migrating tumor cells and the CNS new therapeutic targets. extracellular matrix, and interactions with the immune system (Do tumors activate For example, can lymphocytes be directed resting microglia? If so, how? Do tumors, toward dispersed tumor cells? Can other migratory cells (progenitors) expressing

60 Report of the Brain Tumor Progress Review Group therapeutic 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 Health 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 David Kaplan Evan Snyder Lester Drewes Marla B. Luskin Harald Sontheimer Howard A. Fine Maiken Needergaard Susan L. Weiner Joseph C. Gloriosa Larry Pizzi James E. Goldman Greg Riggins Eric C. Holland David H. Rowitch

STATEMENT OF THE PROBLEM with neural progenitors in the developing CNS? Are distinct tumor The vertebrate central nervous system types derived from: (CNS) is a unique tissue in terms of cell — Multipotent stem cells? number and diversity. During development, — Specified progenitor cells in the major classes of neural cells are derived the developing CNS? from cells of the neuroepithelium. At present — Specified progenitor cells in it is not known how these divergent cell the adult CNS? types are specified and how they relate to — Differentiated cells in the highly heterogeneous brain tumors. There is adult CNS? also a current lack of understanding of the cells of origin and cell lineage associations • What approaches will yield a for distinct tumor types. To design specific comprehensive molecular therapeutic approaches requires a detailed characterization of tumor and normal understanding of the signal transduction neural progenitor cells? What model pathways utilized by different tumor cells in systems are best suited to define tumor regulating cell fate, including cell cell origins? Can human neural stem proliferation and cell death and cells and their derivatives be used in differentiation, as well as a comparison of defining tumor cell origins? these pathways with those utilized by normal neural progenitors. • What extracellular and intracellular signaling systems regulate the fate of An understanding of tumor cell biology brain tumor cells? How are the depends on defining interactions between proliferation, differentiation, and tumor cells and their immediate neural survival of distinct tumor subtypes environment to elucidate how the regulated? Are signaling pathways in environment influences tumor cell behavior tumor cells similar to those utilized by and how tumor cells influence local neural normal neural cells during function. development? Can specific molecular targets be identified in tumor signal CHALLENGES AND QUESTIONS transduction pathways for therapeutic treatments? What are the best cellular • What are the cells of origin that give models with which to address signaling rise to distinct brain tumor types? How issues? do distinct brain tumor types correlate

62 Report of the Brain Tumor Progress Review Group • What are the functionally significant obvious to non–brain tumor cellular interactions between the neurobiologists. founder cells of neural tumors and the RESEARCH AND SCIENTIFIC local neural environment? What are the PRIORITIES physiological properties of distinct tumor cell types? What is the influence Priority 1: of the local neural environment on tumor cells? How do influences of the Create a detailed characterization of the immune system impinge on neural cell of origin of different brain tumor tumor cells? What interactions between types. the endothelium and tumor cells contribute to tumor expansion? What This requires a clear definition of the approaches are required to effectively cellular and molecular characteristics of address interactions between tumor neural cells during development. Basic cells and their environment? biologic studies suggest that tumors might arise from multipotential stem cells, BARRIERS specified progenitor cells in the developing or adult central nervous system (CNS), or • There is extensive cellular diversity dedifferentiation of mature neural cells. To among neural cell types and brain address this issue requires the following: tumor subtypes. • There is a lack of understanding of the • Identification of new cell-surface basic biology of neural cell fate markers and specific receptors for determination, particularly within glial extracellular ligands lineages. • Identification of lineage- and stage- • Insufficient research effort is being specific transcription factors and other brought to bear on the cellular intracellular signaling molecules neurobiology of brain tumors. • Application of these markers for • The lack of interaction between molecular classification of brain neurobiologists and neurooncologists tumors such that relationships between has precluded the effective translation cells at distinct developmental stages of progress in basic research to brain of normal development and tumors tumor research. become apparent • There is a lack of appropriate • Studies of tumor cellular biology molecular screening systems such as provide a potentially important microchip arrays for further approach to defining molecular targets advancement of molecular that could lead to further understanding classification and identification of of normal neural development specific signaling systems. • Analyses of glial development and • There is a lack of appropriate models definition of glial progenitors in the in which to study brain tumor biology vertebrate CNS. This reflects a high • There is a lack of representative cell incidence of glial tumors and the lines in which to study the extrinsic relatively low emphasis on glial and intrinsic signal systems that control progenitor research by the normal and tumor progenitor cell fate. neurobiology community. • Current tissue banks are limited, and their existence or mode of access is not

Neurobiology: Progenitor Cells 63 Resources needed: mitogenic control of tumor and normal neural progenitor cells. To define cellular origins of different brain tumor subtypes, the following resources are A thorough understanding of extracellular required: signaling systems and signal transduction pathways that control progression through • Model development: There is a the cell cycle and specific inhibitors of shortage of effective cell-based progression through the cell cycle is models. Present emphasis is on mouse required. Studies should be directed at and rat models, but the use of other dissecting and identifying targets of cell animals, including zebrafish, dogs, and growth, cell death and survival, and others should not be excluded. New in differentiation in normal and tumor vitro models also need to be progenitors. It seems likely that each distinct developed. Emphasis could be placed tumor type will utilize a different set of on human stem cells/progenitor cells in regulatory signaling pathways and share this system, since species differences some common effector mechanisms. may exist. Progress in this area would Comparison of regulatory signaling be enhanced through the development pathways will lead to enhanced and analyses of multiple model understanding of neural tumors and the systems rather than a focus on a single development of potential targets for specific or restricted number of models or cell intervention strategies. In addition, such lines. studies are likely to provide molecular • Development of microarrays to definitions of progenitor cells at critical generate genetic, molecular, and developmental junctions and may biochemical information. Specifically, characterize their derivative tumors. development of custom-designed neurodevelopment arrays are Resources needed: important. • Tissue banking: Wide access to such Defining the signaling systems involved in tissue resources is critically important. control of normal and tumor progenitor cell • Development of tissue arrays for fate will require the following: further advancement of cellular classification • Additional support for basic biological • Development of infrastructure to research in defining signal transduction encourage interaction between pathways in neural progenitor cells, scientists in basic neuroscience and with particular emphasis on glial neurooncology: These should include progenitors the development of new funding • Facilitation of substantive interactions mechanisms that directly allow among scientists focused on normal interdisciplinary teams of scientist to developmental issues and those address cellular issues of brain tumor focused on glial tumor biology. biology. Organization of specific workshops and the development of joint funding Priority 2: programs between basic and clinical research teams may accomplish this. Develop an understanding of the • Development of microarrays to identify regulation of mitogenic and anti- novel signaling pathways in distinct cell types.

64 Report of the Brain Tumor Progress Review Group • Development of new in vivo and in Resources Needed vitro model systems in which to explore functional requirements for The resources required to address this discrete signaling pathways. research priority include: Specifically, given the limitation of cellular material from distinct tumor • Basic research in non-neuronal cell ion types, a need was recognized to channel expression and function develop new cell lines that more • Models of neovascularization in vitro closely represent native tumor cells by • Identification of the distinct molecular using recently developed molecular properties of brain endothelium, techniques. perivascular astrocytes, and microglia • Facilitation of interactions between Priority 3: neurobiologists, brain tumor biologists, and immunologists through the Understand the interactions of brain development of novel interdisciplinary tumors with their immediate neural funding programs and focused environment. Studies directed at meetings or workshops 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 blood- brain barrier, control of vessel formation, and other aspects of this interaction require additional analyses.

Neurobiology: Progenitor Cells 65 Radiation Biology Co-chairs: Dennis Shrieve, M.D., Ph.D., and Philip J. Tofilon, Ph.D.

Participants: C. Norman Coleman Larry Kun Minesh Mehta Brian Fuller Frederick F. Lang, Jr. Raymond Mulhern Glenn Gobel Bertrand Liang Judith J. Ochs Daphne A. Haas-Kogen Jay Loeffler Ed Oldfield Peter Inskip Lorraine Marin Libby Stevenson

STATEMENT OF THE PROBLEM are inadequate to prevent progression of disease. CLINICAL RADIORESISTANCE OF PRIMARY GLIAL TUMORS In vitro studies of the inherent radiosensitivity of cell lines derived from Radiation therapy is a major component of human glioblastoma multiforme have not the treatment of many primary and demonstrated remarkable radioresistance of metastatic brain tumors. Standard therapy these cells. It is highly probable that the for glioblastoma multiforme and other “neural environment” and microenvironment primary malignant astrocytomas consists of of the in situ tumors, and not just the special radiotherapy after the fullest possible characteristics of tumor cells in culture, surgical resection has been performed. contribute to the remarkable Radiotherapy has long been known to be the radioinsensitivity of gliomas. single most active treatment for these tumors; doses up to about 60 Gy yield dose- NORMAL TISSUE TOXICITY AFTER related increases in survival. RADIATION

Despite this therapeutic benefit, however, in Necrosis and Edema nearly all patients such tumors recur within the volume of tissue receiving high-dose Radiation doses higher than 60 Gy may radiation, and eventually these patients produce vasogenic edema and necrosis in succumb to local disease within a median some patients with glioblastoma multiforme. period of about 12 months. Attempts to Escalation of the radiation dose above this escalate radiation doses above 60 Gy have level poses a significant risk of necrosis. not yielded a significant further advantage in These risks are greater than in patients with survival, probably owing to toxicity related lower-grade astrocytic tumors or non-glial to the volumes of normal brain receiving tumors, which are associated with better doses in excess of tolerance. Conformal prognosis and longer survival. therapies (brachytherapy or radiosurgery), designed to “boost” the local dose, may Functional Deficits allow increased survival. Even after these therapies, however, local failure is the rule Functional deficits in patients after and the risk of radionecrosis is extremely radiotherapy are probably more common high in patients surviving for more than 6 than is currently reported. These deficits months. Even in cases of “microscopic include mental retardation in patients residual disease,” these doses of radiation irradiated as infants, learning disabilities in

66 Report of the Brain Tumor Progress Review Group older pediatric patients, and memory or milieu is crucial to the behavior of cognitive deficits in adults. Whole-brain central nervous system tumors. Cell radiotherapy for metastatic disease can result culture studies are insufficient to allow in a range of neurocognitive outcomes, understanding of the interactions ranging from little or no deficit to full-blown between tumor and normal tissue, dementia. The factors contributing to the which is key to studying the development of neurocognitive deficits are mechanisms of resistance and thereby poorly understood. These deficits have to improving treatment. It is important severe effects on quality of life for patients to describe in situ the physiology of and their families. these tumors, which is probably involved to a great degree in their CHALLENGES AND QUESTIONS resistance. Imaging is available, but interactions between normal and tumor • Lack of understanding of cells must be described and modeled. mechanisms of tumor Better models—specifically, orthotopic radioresistance and normal tissue tumor models rather than subcutaneous toxicity—Little is known of the basic models, and practical models for mechanisms by which radiation kills studying late damage to the brain—are brain tumor (or other) cells. Two main necessary to study these interactions. types of cell death, however, are thought to be important: mitotic, or • Low enthusiasm for development of clonogenic, death (loss of the ability to drugs or modulators of divide) and apoptosis (programmed radiosensitivity—There is little cell death). There is evidence that enthusiasm within the pharmaceutical malignant glioma cells do not undergo industry for the development of drugs significant apoptosis after irradiation. or modulators of radiosensitivity for Clearly, in patients, many cells escape brain tumors. Incentives and both modes of cell killing after encouragement for industry radiotherapy. The “neural involvement in brain tumor research environment” appears to play an are needed. The National Cancer important role in this clinical Institute (NCI) is planning to establish radioresistance, as may a screening program to test drugs in the microenvironmental factors. In clinic for their potential as addition, the fundamental processes radiosensitizers. involved in the development of normal tissue toxicity after radiation are not • Inability to test new drugs designed understood. to work with radiation—It is difficult to test new drugs designed to work • Lack of integration of neurobiology with radiation. Combination with radiobiology—There would be a development at preclinical stages great advantage to integration of basic currently does not occur. The Food and and brain tumor neurobiology and Drug Administration focuses on single brain tumor–related radiobiology. agents rather than on combined- modality therapies. Furthermore, many • Unavailability of appropriate companies are apprehensive about models—Appropriate animal models studying their agents in combination are not available, hindering progress. with radiation because of concern that The brain is a unique organ, and its toxicity could be, or appear to be,

Radiation Biology 67 enhanced. This means that, owing to • Develop and validate appropriate regulatory complications, models. pharmaceutical companies will not Priority 3: study combined modalities as first- strike therapies. Establish clinical indicators of radiation response of tumor and normal tissue. RESEARCH AND SCIENTIFIC PRIORITIES • Develop imaging modalities to assess tumor response and early changes that Priority 1: are predictive of late sequelae. • Identify serum, cerebrospinal fluid, or Overcome radioresistance of primary tissue markers of tumor or normal brain tumors. tissue response. • Develop methods of target • Delineate the mechanisms of inherent “credentialing”—identification of radioresistance. target molecules, evidence of • Define the influence of the neural modification of the target molecule, environment on radioresistance of and measurement of desired effect. brain tumors. • Develop high-throughput techniques to • Identify molecular targets for assess the efficacy of modulators of modulation of brain tumor radiosensitivity (e.g., microarray radiosensitivity. technologies). • Develop hypothesis-driven • Establish the use of clinical correlates combinations of radiation therapy and to validate preclinical studies. modulators to overcome resistance in • Develop predictors of sensitivity clinical practice. (tumor versus normal tissue). • Develop and validate appropriate models. RESOURCES NEEDED

Priority 2: • NCI program for the development of drugs, sensitizers, and/or modulators of Overcome normal tissue toxicity radiosensitivity (necrosis/edema versus functional • Ability to test drugs in combination deficits). with radiation • NCI-sponsored workshop bringing • Delineate the molecular, cellular, and together neurobiologists and physiological processes leading to radiobiologists to discuss strategies for radiation-induced toxicity. investigating brain tumor • Define the influence of radioresistance and radiation-related neurodevelopmental stage on these toxicity processes. • Delineate the interactions between tumor and normal cells in the development of radionecrosis. • Develop hypothesis-driven interventional strategies (radioprotection).

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 Dennis C. Shrieve Joseph C. Gloriosa Malcolm Smith Stuart A. Grossman Philip J. Tofilon Alison Hannah Diane Traynor Peter T.C. Ho Michael Walker William G. Kaelin, Jr. Roy S. Wu David Kaplan Mark Yarborough Kathleen Lamborn John S. Yu Bertrand Liang W. K. Alfred Yung

BACKGROUND: STATUS OF THE cellular/molecular correlates of disease FIELD characteristics and therapeutic response.

Surgery Radiation Oncology

The tremendous evolution in surgical Technology has also driven the field of capabilities of recent decades has been radiation oncology. Radiation therapy has driven by technology. The advantage of proven efficacy in many common tumor maximal resection has been documented in histiotypes. Trials in malignant gliomas in most primary central nervous system (CNS) particular have provided opportunities to test tumor systems. At present, the state of the altered fractionation and three-dimensional, art in treatment for brain tumors is the image-guided delivery (including conformal incorporation of preoperative imaging, both photon irradiation, radiosurgery, and metabolic and functional, with image-guided brachytherapy) to achieve substantial dose surgical techniques. For example, escalation. Unfortunately, however, there are “navigation” technology allows imaging in a few data encouraging additional patient by using external landmarks before explorations of dose escalation with surgery, and during surgery, the surgeon is radiation therapy alone for these inherently guided to the lesion and can appreciate its resistant tumors. Further studies of enhanced extent based on the preoperative image set. radiation dose are ongoing in other The newest technologies provide histiotypes (e.g., low-grade gliomas, and intraoperative imaging, allowing the ependymomas). neurosurgeon to realign the three- dimensional image set during surgery, Interactions of radiation with further enhancing safe maximal resection. pharmacological and biological agents Surgery can also be important in local drug represents an important area for further delivery, including the strategic placement development. Understanding ways to of catheters to deliver small molecules. increase tumor response and potentially to Careful and consistent mapping of tumor limit normal tissue toxicities requires specimens allows coordination with additional laboratory and clinical testing. imaging, drug delivery, and Explorations of genetic radiosensitization

Treatment 69 offer exciting research opportunities in the • There are few active therapeutic malignant gliomas. approaches or agents for the treatment of brain tumors. In pediatric tumors, trials of restricted • There are no adequate or reliable volumes of radiation therapy and dose preclinical screening systems. reductions defined by response to • Few new agents are marked for CNS chemotherapy seek to improve the tumor development. therapeutic ratio in tumor types with known • There is little understanding of drug- radioresponsiveness (e.g., medulloblastoma, radiation interactions in normal CNS other embryonal tumors, low-grade gliomas, tissue. intracranial germ cell tumors). Exquisite localization of radiation volume in CHALLENGES AND QUESTIONS ependymomas is the basis for ongoing and planned trials even in very young children. Few Active Therapeutic Approaches or Image definition of tumor extent is Agents for the Treatment of Brain important in guiding restricted radiation Tumors therapy volumes; better assessments of tumor volumes and margins are needed. Generally, there have been few significant advances in the treatment of malignant Chemotherapy gliomas over the last two decades. Difficulties in identifying effective Chemotherapy has had a significant impact approaches include heterogeneity of tumor on the treatment of selected CNS tumors, types, the rarity of some tumors, and relative such as primary CNS lymphomas, anaplastic difficulties in accruing adult patients to oligodendrogliomas, and pediatric clinical trials. All of these problems result in embryonal tumors. Nevertheless, the exact small patient populations for clinical study. drug regimen, timing, and duration of treatment remain areas of uncertainty. There are a myriad of biological reasons for Despite the clear benefits for these selective the ineffectiveness of most current tumor types, the role of standard chemotherapeutic agents. These include chemotherapy is limited for the majority of inconsistent drug delivery secondary to primary CNS tumors, particularly tumors of issues related to the blood-brain and blood- the astrocytic lineage. Identification of the tumor barriers, tumor hypoxia, intrinsic drug role of chemotherapy has been hampered by resistance, and acquired drug resistance relatively small numbers of many brain through the variable exposure of tumor cells tumors other than glioblastoma multiforme, to different concentrations of delivered drug making large randomized trials problematic, as a result of problems with drug delivery. and by the apparent poor responsiveness of glioblastoma multiforme to cytotoxic The “new biology” has led to the chemotherapy. identification of a number of new signaling pathways that appear to be important for STATEMENT OF THE PROBLEM gliomagenesis, and with their identification has come the creation of a number of new The main problems in brain tumor treatment and exciting molecular inhibitors of those research listed below are addressed in detail pathways that appear to represent exciting in the following section (see “Challenges therapeutic opportunities. There is and Questions”). 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, brain tumors could move forward quickly patient accrual, and endpoint assessment, and effectively. may be suboptimal for studying newer cytostatic agents for brain tumors. As a Few New Agents Marked for CNS Tumor result of this concern, there is reluctance Development from private industry (the source of the majority of the newer anti-tumor agents) to Novel therapeutic development for CNS invest resources into exploring the utility of tumors is modest, and progress has been these agents in patients with brain tumors. meager. Despite the exciting advances made in the identification of potentially active, No Adequate or Reliable Preclinical selective, rationally designed anti-cancer Screening Systems agents, there has been significant reluctance on the part of the pharmaceutical industry to Preclinical screening of potential agents is move these agents into the brain tumor currently time consuming and inefficient. population. The reason for this reluctance Spontaneously occurring brain tumor animal relates to the inherent characteristics of brain models are not available at present, and tumors and of patients with these tumors, there is a growing belief that currently which make them problematic as the focus utilized xenograft models do not accurately of industry research. Examples include reproduce the biology of human tumors and difficulties quantifying toxicities in patients therefore are generally nonpredictive for with brain tumors, the altered pharmacology identifying active clinical agents. Therefore, of many agents secondary to induction or the routine use of these models for screening inhibition of the hepatic P450 cytochrome agents for clinical development not only system from concurrent administration of may have allowed inactive agents to enter anti-epileptic agents, the heterogeneity of the clinical trials in the past, but may have patient population (particularly as it relates inadvertently excluded potentially active to heterogeneity of tumors), modest numbers drugs from ever having been evaluated of patients, and slow patient accrual, clinically. This problem has become although this last issue has been addressed in increasingly more important as the number part by the brain tumor consortia. of rationally designed agents with cytostatic rather than cytotoxic mechanisms of action Low Rate of Patient Accrual to Clinical are being developed (e.g. anti-angiogenic, Trials differentiating, anti-invasion agents). Such agents can be adequately tested only in vivo, Patient accrual into clinical trials in general making the lack of reliable tumor models a is lacking: less than 10% of adult patients major obstacle for preclinical development. with brain tumors enter clinical trials. Ways Clearly reliable in vitro and/or tissue should be investigated to systematically surrogate markers and/or assays of increase adult patient accrual to trials. Even biological activity would be very helpful for though there are at present few novel the preclinical and clinical development of approaches that warrant large-scale Phase III these agents (see “Few New Agents for CNS trials, the infrastructure for speedy accrual Tumor Development”). Coupled with the needs to be in place in order to expedite establishment of biological endpoints testing when new agents appear promising in correlated with survival, improvements in pilot studies. In addition, determining groups preclinical screening may lead to innovative of molecularly homogeneous tumors would clinical trial designs, and ultimately the allow for more, and more effective, clinical entire field of therapeutic development for trials.

Treatment 71 Improvements in “response” criteria are radiographic demonstration of diminished needed. To advance the field of novel blood flow after administration of an therapeutic agents for brain tumors, it will antiangiogenic agent). Ideally, such be necessary to identify and validate endpoints will have correlates to preclinical meaningful biological endpoints for screens (e.g., the same endpoint used to evaluating novel therapies. There continues screen and select a biological agent for to be significant discussion within the clinical testing can be demonstrated to be neurooncology and neuroradiology modulated in the treated patient). Such community as to the appropriate criteria for endpoints could include (but are not limited measuring radiographic tumor “response.” to) in vitro assays with patient material This discussion arises from the realization (blood, urine, cerebrospinal fluid, tumor that abnormalities detected by magnetic tissue) and imaging methodologies such as resonance imaging and computed magnetic resonance spectroscopy or positron tomography and associated with tumors may emission tomography with appropriate be the result of pathophysiological processes probes. Early clinical trials could be other than the tumor mass itself. These designed to allow for agents that achieve a abnormalities include treatment-related specific threshold effect in the effects (e.g., radiation necrosis), cerebral predetermined endpoint evaluation to move edema, inflammation, and postsurgical forward into further clinical development, changes. Routine criteria for measuring ultimately leading to a definitive Phase III perpendicular diameters may be limited in trial. reliability and accuracy by the fact that brain tumors often grow as irregular, asymmetrical The development of large, historical, clinical processes in three dimensions, and by trials is important in order to evaluate the variability in head positioning in sequential use of endpoints such as time to tumor imaging studies. The problem is further progression and survival in early-phase compounded by the realization that many of trials. Such evaluations must be based on the novel agents entering clinical trials will meaningful historical data used as controls not necessarily have cytotoxic mechanisms against which activity and efficacy of the of action, so it might be difficult to assess agent can be preliminarily inferred. Clinical therapeutic activity within the first several endpoints for evaluating new agents must months of therapy, even with highly reliable include quality of life measures in all Phase measurement techniques. This difficulty in III and novel Phase II trials. The importance turn may complicate early (Phase I and II) of quality of life endpoints is readily trials, in which too few patients may be apparent in pediatric tumors but are also treated for a sufficient period to allow an relevant for malignant gliomas in adults. accurate assessment of effects on progression-free and overall survival, the The development of such endpoints and most accurate and important measures of objective response criteria will not only aid biological activity for a cytostatic agent. in the development of novel agents but also allow for the accrual of knowledge about For this and other reasons outlined below, it current therapies. Furthermore, they will would be ideal if, in early-phase studies, allow earlier identification of response in novel endpoints could be used as measures individual patients. Determining which of biological activity of the tested agent. patients are helped by current therapies and Such endpoints optimally would be related why will aid more rational and focused to the mechanisms of action of the agent or development of new therapeutics. to modulation of the putative target (e.g.,

72 Report of the Brain Tumor Progress Review Group Novel clinical trial designs should be based pharmacological agents should encourage on the demonstration that a new agent is pharmacokinetic and scientific endpoints, able to reach and affect its intended target. including collection of tumor and, where The rarity of most CNS tumor types and the appropriate, adjacent normal neural tissue lack of meaningful short-term endpoints for pharmacological and genetic studies after correlated with survival lead to difficulties drug delivery. Involvement of neurosurgeons in designing timely and effective brain and basic scientists in the design and tumor clinical trials. In order to focus more analysis of clinical trial may facilitate this quickly on the highest-priority agents, objective. especially for less common or slowly growing brain tumors, it would be helpful to Little Understanding of Drug-Radiation be able to select them for further study based Interactions in Normal CNS Tissue on demonstration of their ability to actually reach and alter their putative molecular An important challenge remains the targets in patients. development of interventions that might enhance radiosensitivity while diminishing An additional issue relates to the delays neurotoxicity. Spatially defined radiation often encountered in developing interactions with pharmacological and combinations of new agents. Rational biological agents represent an exciting area combinations may be expected to be no less for potential enhancement of the therapeutic important for newer drug classes directed at ratio in brain tumor treatment. Further defined molecular targets than they are for understanding of the interactions of conventional cytotoxic chemotherapies. chemotherapeutic agents and irradiation in However, the current regulatory system normal CNS tissues should be sought. requires that drugs can be licensed only if they are sufficiently useful individually, New avenues to exploit radiation effects even when combinations may reasonably be require intensive laboratory development expected to be considerably more prior to expedited clinical trials in malignant efficacious. To substantially speed the gliomas. Such approaches include the development cycle for effective delivery of tumorsensitizing or - combinations would require a systematic neuroprotective molecules via gene therapy plan for combination testing that begins at coupled with focal radiation delivery. the preclinical and Phase I and II levels of Exploration of radiation-induced promoters the process, and when carried out with represents an additional focal biological appropriate rigor, acceptance of such a effect that may be exploited in this tumor strategy by the Food and Drug system. (See also the report of the Radiation Administration. Biology breakout session.)

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

Treatment 73 RESEARCH PRIORITIES • Provide added resources to facilitate moving new therapeutic agents Priority 1: developed in the academic setting from laboratory compounds to clinical-grade Facilitate novel therapeutic development drugs for therapeutic trials. and increase knowledge about the mechanisms of current therapies. • Increase patient accrual into clinical trials. • Enhance preclinical screening: — Increase patient awareness of — Recognize that currently clinical trials and the benefits existing brain tumor animal of participation through models are unreliable advocacy groups. predictors of clinical drug — Support a systematic effort to activity. determine barriers to adult — Develop a paradigm to move enrollment in brain tumor rationally developed new clinical trials, the results of agents toward clinical trials which effort should be primarily based on their incorporated into educational ability to inhibit signaling and informational efforts to pathways that are known to increase enrollment. be important in the — Facilitate the availability of proliferation and/or survival innovative studies for less of gliomas or other CNS common CNS tumors or tumors. Such a paradigm will inclusion in ongoing trials of require validation by promising new therapies for experience, however, and more common CNS tumors perhaps could never displace in which patients can be entirely older designs, analyzed as distinct because our understanding of subgroups. pathways and molecular targets is far from complete • Identify meaningful biological and will always be changing. endpoints for the evaluation of new Some agents will eventually therapeutic approaches. be found to modulate — Develop and validate pathways or inhibit targets in molecular and genetic ways other than those endpoints (surrogate originally assumed and markers). intended. — Develop and validate imaging — Support the development of endpoint parameters (e.g., new animal models that more quantitative magnetic faithfully model human resonance imaging and tumors as validated both by magnetic resonance molecular characterization spectroscopy). and through their pharmacological interactions • Optimize study designs. and response to new and — Identify genetic and known cytotoxic agents. epigenetic markers that more accurately group patients

74 Report of the Brain Tumor Progress Review Group with biologically • Support enhanced research into homogeneous tumors. potential means of neuroprotection. — Formulate study designs by • Support research to improve the design using specific biological and delivery of conditionally endpoints that are relevant to replicating oncolytic viral vectors and the known mechanism of other gene therapy vectors used either action of the agent(s) being alone or in conjunction with tested. chemotherapy and/or radiotherapy. — Encourage study designs that incorporate tissue acquisition Priority 3: before and during treatment for assessment of drug Enhance research to improve the delivery and measurement of therapeutic ratio for radiation therapy biological endpoints. for CNS tumors. — Consider distinct designs appropriate to cytostatic and • Study means of enhancing cytotoxic agents. radiosensitivity for malignant gliomas — Encourage incorporation of and other CNS tumors. functional and quality-of-life — Develop gene transfer measures in adult and technologies providing pediatric brain tumor studies. radiosensitization or — Identify common data radioprotection. elements to facilitate the — Explore the role of radiation- evaluation of new therapies inducible promoters as a across institutions and means of enhancing temporal cooperative groups. and spatially specific gene — Establish a national data expression. repository for clinical and genetic information to be • Study outcomes in children treated available to investigators. with limited volume, high-technology radiation therapy, often at less than Priority 2: “conventional” dose levels.

Stimulate research on improving the RESOURCES NEEDED therapeutic index of new agents specifically relevant to the CNS. • Resources to establish an Internet- based clinical/research database • Develop improved methodologies for • Incentives to encourage industry drug delivery (e.g., blood-brain barrier interactions with academic disruption, convection) for both investigators to identify new endpoints primary intraparenchymal tumors and and surrogate markers important to leptomeningeal tumors. testing new CNS agents • Develop new methodologies for • Increased access by academic scientists assessing neuropharmacokinetics. to centrally funded GMP capabilities in • Develop tools for assessing toxic developing new CNS agents effects of drugs on the CNS • Funding for the development and (neurotoxicology). 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 radiation- inducible 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 Andreas Kurtz Sandra Rempel Webster Cavenee Linda M. Liau Tom Rozman E. Antonio Chiocca Craig Lustig John H. Sampson Pam Del Maestro Robert L. Martuza Arthur W. Toga Richard A. Fishel Ed Oldfield Mark Yarborough Ramon Gilberto Gonzalez Luis Parada Han Ying James F. Gusella David Parkinson Richard Youle Bruce R. Korf David Ramsay

STATEMENT OF THE PROBLEM treatment for these neoplasms, some cannot be resected and others may recur despite A wide variety of extraaxial tumors arise in resection. Furthermore, some of these the spinal and cranial nerves and sometimes tumors remain dormant and do not require affect the brain by compression. Extraaxial intervention, whereas others may grow and tumors are uniquely interesting for brain become refractory to standard therapy. tumor research for a number of reasons: Unfortunately, current neuroimaging • Extraaxial tumors tend to be more techniques do not provide substantial homogeneous than parenchymal brain preoperative information about the predicted neoplasms such as gliomas. rate of tumor growth or the likelihood of • The location of extraaxial tumors tumor recurrence, and current extrinsic to the brain encourages novel histopathological classification and grading approaches to targeted therapy and are not adequately predictive in many cases. facilitates acquisition of tissue for Longitudinal studies of tumor growth are research. hampered by the sometimes long intervals • The early genetic changes underlying between presentation and recurrence, and some extraaxial tumors are well many standard registries do not capture characterized, including in hereditary information on these lesions. Finally, syndromes, such as neurofibromatosis ancillary therapies are primarily restricted to 2, that predispose to these lesions. radiation therapy, and few other options are available. Extraaxial tumors that affect the brain and spinal cord include meningiomas, CHALLENGES AND QUESTIONS schwannomas, neurofibromas, and pituitary tumors, as well as mesenchymal tumors of • To predict which meningiomas and the skull, spine, and dura mater. Although schwannomas will remain dormant and all of these entities may present problems in will not require surgical clinical management, two lesions, intervention—Such information will meningiomas and schwannomas, are direct surgery toward those patients priorities for further research because they who are most likely to benefit from it are common and may be difficult to manage. and will spare potential complications Although surgical resection is a mainstay of for other patients.

Extraaxial Brain Tumors 77 • To predict which meningiomas and and of unique populations of patients, schwannomas will have a greater such as those with neurofibromatosis 2. likelihood of recurrence after surgical Priority 2: resection—Such information would allow follow-up strategies and Develop outcome measurements for therapies to be directed toward those evaluating the efficacy of therapies for patients in need while sparing extraaxial tumors and the effects of tumor unnecessary therapy and potential and therapy on quality of life. complications for those patients whose tumors will not recur. Priority 3: • To develop novel therapies for meningiomas and schwannomas that Develop novel therapies for extraaxial are not amenable to surgery or that tumors on the basis of on their unique recur after surgery—Current biological qualities. approaches are primarily restricted to radiation therapy, which also has • Molecular biological research should potential neurotoxicity in extraaxial elucidate the pathways responsible for lesions. meningioma and schwannoma • To identify clinical and neuroimaging tumorigenesis. Initial avenues for endpoints for the evaluation of research would include study of meningioma and schwannoma growth pathways regulated by merlin (the and of therapeutic efficacy—Current protein encoded by the endpoints, such as tumor growth, time neurofibromatosis 2 gene). Such to recurrence, and survival, are information could contribute to problematic given the slow growth biologically rational approaches to characteristics of many of these therapy. tumors. • Targeted therapies should be investigated on the basis of the RESEARCH AND SCIENTIFIC localized and physically separate PRIORITIES nature of these tumors, as well as on their biological characteristics. A wide Priority 1: variety of therapeutic approaches could be of interest, from small-molecule Understand the natural history of inhibitors to antiangiogenesis to meningiomas and schwannomas, as well immunological to gene therapy. as their response to therapies. RESOURCES NEEDED • Neuroimaging strategies should be developed that will allow prognostic • Integrated registries, tissue banks, and information, anatomical or molecular, databases for meningiomas and to be derived before surgical schwannomas, including intervention. neurofibromatosis 2 • Tissue-based approaches should focus • Funding mechanisms to support long- on refined diagnoses based on term (e.g., >10-year) longitudinal molecular profiling. studies of tumor growth rates and the • Population-based studies must be natural history of tumors in specific enabled to allow follow-up of large patient populations (such as those with numbers of patients over long periods 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 Peter Ho Edward A. Neuwelt Mitchel Berger Fred Hochberg Lawrence Pizzi Rebecca Betensky Susan Hockfield Jasti S. Rao Pim Brouwers Eric C. Holland Greg Riggins Peter Burger William G. Kaelin Jr. Elizabeth Stevenson J. Gregory Cairncross Kathleen Lamborn Michael Walker Webster Cavenee John Mazziotta Albert Wong R. Edward Coleman Minesh Mehta Roy S. Wu Ronald A. DePinho Ravi Menon W. K. Alfred Yung Howard A. Fine Christina A. Meyers Candece Gladson Maiken Needergaard Joseph C. Gloriosa Donna Neuberg

STATEMENT OF THE PROBLEM are small, and no single institution acquires adequate numbers to answer important Intraaxial tumors comprise a complex questions. mixture of low- and high-grade lesions occurring in both children and adults. This Tissue for study is limited. Often only a report restricts its discussion to adult tumors needle biopsy is available, and sometimes, other than malignant gliomas, specifically as in infiltrating low-grade gliomas, no low-grade gliomas, lymphomas, and germ tissue is available. This creates particular cell tumors. challenges for molecular studies. Imaging techniques may provide an alternative Low-grade gliomas can be divided into two approach for the investigators to non- general categories: infiltrating and localized. invasively “examine” the entire tumor. Infiltrating tumors include, but are not Development of biological and molecular limited to, fibrillary astrocytomas, imaging technologies is essential for further oligodendrogliomas, and ependymomas. understanding of these less common Non-infiltrating tumors include pleomorphic intraaxial neoplasms. xanthoastrocytomas, pilocytic astrocytomas, and dysembryoplastic neuroepithelial RESEARCH AND SCIENTIFIC tumors. Despite their rarity, primary central PRIORITIES nervous system (CNS) lymphomas and germ cell tumors are also important because some Low-Grade Gliomas patients are cured of their tumors. However, not all patients are cured, and some of those Priority 1: who are suffer long-term neurotoxicity. Better understand the natural history of CHALLENGES low-grade gliomas with an emphasis on mechanisms of progression, infiltration or Although numerous in the aggregate, each lack of it in non-invasive diagnosis. tumor type is uncommon. Patient numbers

80 Report of the Brain Tumor Progress Review Group Imaging strategies should be developed Priority 4: to: Develop more effective therapies. • Identify the extent of infiltrating tumor • Predict progression • Conduct long-term studies on dose • Identify heterogeneity prior to surgery intensity for the treatment of or biopsy lymphomas and determination of optimum volume for radiation therapy Priority 2: for germinomas. • Determine the relationship between Develop techniques to molecularly molecular characterization of the tumor characterize tumors on small biopsy and response to therapy is required. samples. • Long-term studies of neurotoxicity require development of quantitative • Particular emphasis should be placed quality of life and neurocognitive on the molecular signature of tumors instruments, development of treatment that infiltrate and progress to higher strategies to improve cognition, and grade. further study on how the tumor itself • Conduct population-based studies to may affect brain function. allow assessment of etiology and new treatment strategies, including their RESOURCES NEEDED toxicity and patients’ quality of life. • Funding for the establishment of cell Primary CNS Lymphoma and Germ Cell lines of each of these tumor types is Tumors necessary to learn more about the biology of these tumors. Priority 3: • A central repository for tissue banking for genetic analysis of tumors should Understand the natural history of be established to draw samples from all primary CNS lymphomas. over the country. • A central registry or database should be • Epidemiologic studies are needed to established to accumulate clinical identify environmental factors other information on diagnosis, response to than immune suppression that appear treatment, neurotoxicity, and long-term to be leading to an increased incidence follow-up of patients with these of lymphomas. tumors. Support should be provided for • Molecular characterization of CNS long-term longitudinal studies. 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.

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

Participants: Darell D. Bigner Brian Fuller Harald Sontheimer Peter M. Black Peter Inskip Philip J. Tofilon Ronald G. Blasberg Lois Lampson Jeannine Walston Carol Kruchko Jay Loeffler Carol Wikstrand Rolando Del Maestro William M. Pardridge Jeanne Young Glenn Dranoff Lynn A. Ries John S. Yu Lester Drewes

STATEMENT OF THE PROBLEM CHALLENGES

Central nervous system (CNS) metastases The main problem in the area of CNS are a serious and common problem in metastatic disease is the scarcity of data on patients with systemic cancer. Brain the biology of the disease that can be applied metastases are at least 10 times more to clinical approaches to prevention and frequent than primary brain tumors. treatment. Other challenges are as follows: Leptomeningeal metastasis affects about 5% of cancer patients, and spinal cord • Obtaining tissue from both the primary compression due to metastases occurs in tumor and the CNS metastasis in order 5–10% of patients with systemic to understand the fundamental biology malignancies. Despite refinements in surgery of metastases to the nervous system. and radiotherapy, many patients die from • Including patients with CNS metastasis CNS metastases, and long-term survivors in protocols for treatment of systemic often suffer devastating side effects of their disease. All too often, innovative treatment. protocols for the treatment of cancer specifically exclude brain and other Despite the large number of patients CNS metastases because of the belief affected, metastatic disease to the that metastases in the CNS do not nervous system is an area that has been respond to treatments that affect the largely neglected by investigators. CNS cancer elsewhere in the body. metastases are an “orphan” area falling • Increasing the interest of the between the classic areas of tumor neuroscience and neuro-oncological biology/medical oncology and neuroscience, community in the biology and as shown by the dearth of extramurally treatment of CNS metastases. funded grants in the National Cancer Institute (NCI) and National Institute of RESEARCH AND SCIENTIFIC Neurological Disorders and Stroke (NINDS) PRIORITIES portfolios. As a result, understanding of the general cellular and molecular mechanisms Priority 1: involved in metastasis has lagged behind that of other advances in the basic sciences Identify genetic/cellular/molecular factors related to oncology and neuroscience. 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 C. David James Sarah Nelson Dennis C. Shrieve David Ashley David Kaplan Judith J. Ochs Malcolm Smith Jaclyn A. Biegel Kenneth A. Krohn Scott Pomeroy Evan Snyder James Boyette Larry Kun Sam D. Rabkin Diane Traynor Greta Bunin Frederick F. Lang Richard Ransohoff Richard Vallee Tom Curran Marla B. Luskin Lucy B. Rorke Jeanne Young Henry Friedman Lorraine Marin Bruce Rosen Susan L. Weiner James Goldman Robert H. Miller David H. Rowitch Daphne A. Haas- Sherie Morrison James Rutka Kogen Raymond Mulhern Gail Segal Alison Hannah Mark A. Israel

STATEMENT OF THE PROBLEM nervous system early in the course of illness. Whereas 90% of adult tumors arise in the Childhood brain tumors are the second most cerebral cortex, 50% of childhood brain frequent malignancy of childhood and the tumors originate infratentorially, in the most common form of solid tumor. Tumors cerebellum, brain stem, or fourth ventricular of the central nervous system (CNS) region. A large proportion of brain tumors in comprise 22% of all malignancies occurring adults are the result of metastatic lesions among children up to 14 years of age and from nonprimary brain sites, and the primary 10% of tumors occurring among 15–19- tumors are for the most part glial tumors and year-olds. Although rapid progress has been meningiomas. In contrast, childhood brain made in the treatment of some forms of tumors mainly represent primary CNS childhood cancer, such as acute lymphatic lesions and, although gliomas make up the leukemia, the outcome for children with majority of childhood neoplasms, other primary CNS tumors has remained poor and tumor type,s such as medulloblastomas, for most tumors has not changed over the primitive neuroectodermal tumors, past decade. Brain tumors are now the pineoblastomas, atypical teratoid tumors, leading cause of death from childhood and other embryonal neoplasms, contribute a cancer, accounting for 24% of cancer-related significant proportion. deaths in 1997 among persons up to 19 years of age. In addition, due to either the effects The biological behavior and management of of the tumor or the treatment required to childhood tumors depends on not only the control it, survivors of childhood brain histological character of the tumor but also tumors often have severe neurologic, its location within the nervous system. For neurocognitive, and psychosocial sequelae. example, childhood low-grade cerebellar gliomas may be curable in over 90% of Tumors in childhood differ significantly patients with surgery alone, whereas brain from adult lesions in their sites of origin, stem gliomas (even if “low-grade”) carry the histological features, clinical presentations, dismal prognosis of death for most child and proclivity to disseminate throughout the patients within 18 months of diagnosis. The

84 Report of the Brain Tumor Progress Review Group aspects of tumor dissemination are include such rare tumors, which results in extremely important for childhood brain missed opportunities to understand these tumors. Control of local disease remains tumors’ biology and create more effective problematic for many forms of childhood treatment regimens. brain tumors; however, specific types of tumors, especially embryonal tumors, have a Even within the tumor types commonly high proclivity for early dissemination found in both children and adults, studies within the nervous system and treatment focusing on tumors occurring in adults may approaches must take into account this not result in new insights for pediatric tendency for early tumor spread. The tumors. The molecular aspects of glial neurobiological underpinnings of these neoplasia in children, for example, appear to differences are largely unknown: the differ substantially from those in adults. importance of the relationship between Most childhood low-grade gliomas are tumor type and location is poorly studied; pilocytic astrocytomas, whereas this tumor the reasons why tumors primarily arise at type is relatively infrequent in adults. certain ages and have proclivity to specific Pilocytic astrocytomas have a different areas of brain are unclear; and the ways to biology than fibrillary or other grade 2 utilize these differences to alter management lesions. For example, one major difference and improve outcome require further is that pilocytic astrocytomas rarely mutate investigation. into higher-grade lesions, whereas fibrillary astrocytomas often do so. Furthermore, even The histological heterogeneity of childhood fibrillary low-grade gliomas in childhood brain tumors makes it necessary to develop rarely mutate into higher-grade tumors in the separate lines of investigation into the childhood years, despite this common molecular mechanisms of each type of occurrence in adults. For progress to be tumor, the effect of the surrounding milieu made in this subset of tumors, research must on the tumor, and the development of be focused directly on pediatric low-grade effective treatment approaches. A variety of gliomas. different classification systems have been utilized for childhood brain tumors, and The differences between the neurobiological controversy still exists concerning the most features of glial neoplasia in children and appropriate nomenclature for some tumors. those of the disease in adults are not limited The classification systems in use are still to low-grade tumors. Approximately 40% of based on relatively subjective criteria, grade IV gliomas in adults exhibit making comparison across different studies amplification of epidermal growth factor difficult. Although some subtypes of receptor, whereas this change is less childhood brain tumors are relatively rare, commonly detected in childhood such as primitive neuroectodermal tumors glioblastomas. In addition, P53 mutations, (excluding medulloblastoma), atypical which are observed in 50% of grade III and teratoid tumors, medulloepitheliomas, grade IV gliomas in adults, are rarely seen in dysembryoplastic neuroepithelial tumors, high-grade gliomas in children. These desmoplastic infantile gangliogliomas, and differences may at least partly account for superficial cerebral astrocytomas of infancy, the somewhat better prognosis for childhood together they constitute a significant high-grade gliomas; a subset of children percentage of childhood brain tumors and a with high-grade glial tumors, including major cause of morbidity and mortality. glioblastoma multiforme (as high as 20% in Studies focusing on the more frequent adult some studies), survive after treatment. In and pediatric CNS tumors often do not addition, evidence from randomized

Pediatric Brain Tumors 85 prospective studies shows that long-term abnormalities have been noted in these survival for childhood glioblastoma primitive neuroectodermal tumors, and multiforme is improved by the addition of research into the molecular pathways chemotherapy to radiotherapy; such data are involved in tumor development and growth lacking in adults. is needed.

A focused effort to define relevant molecular Infants and very young children with markers for prognosis in childhood glial primary CNS tumors often harbor lesions tumors may facilitate improved diagnostic that are apparently unique to the early and therapeutic stratification of patients and childhood years. Some of these tumors, such more appropriate treatment. Treatment as atypical teratoid tumors and strategies may also need to differ for medulloepithelioma, although rare, are a childhood and adult high-grade gliomas. significant problem in the pediatric age Also needed are innovative classification range. More global investigations into brain systems that integrate molecular, tumors, especially research focusing on neurobiological, and neuroimaging aspects more common adult tumors, will fail to with histological diagnosis to develop more address these important lesions. Many of clinically relevant nomenclatures for these these embryonal tumors are apparently true tumors; this will guide epidemiological congenital tumors, and studies of the research, biological studies, and treatment mechanism of their development may also approaches. lead to important insights into general brain development. Similarly, studies of brain The molecular pathways involved in the development may lead to insights into the development of primitive neuroectodermal neurobiological aspects of these and other tumors are just being unraveled. Research embryonal tumors. focused on the glial tumors that predominate in adults may not lead to a better Also related to age are the effects of therapy understanding of these primitive embryonal on the developing nervous system. As stated tumors. Although such tumors are not previously, some childhood brain tumors are unique to childhood, they are substantially true congenital lesions, whereas others, such more common in children than in adults. as medulloblastoma and ependymoma, peak There has been significant controversy over in incidence before age 5 years. Given the the most appropriate classification of proclivity of primitive tumors to disseminate childhood primitive neuroectodermal within the nervous system early in the course tumors, primarily whether all such tumors of disease, treatment approaches must focus should be grouped into one category or on controlling not only local disease but also better subdivided based purely on tumor disease in all sites of the nervous system. location. Recent studies have suggested, This often requires treatment to be aimed at although not proven, that although these the entire nervous system in the young child tumors share histological similarities, and heightens the likelihood of treatment- molecular features of the lesions occurring related brain injury. outside the posterior fossa are distinct from those arising in the posterior fossa. In The long-term effects of the tumor and its addition, studies have recently shown that treatment on outcome are extremely other molecular features, such as TrkC important issues in both children and adults expression, correlate with outcome in with brain tumors, but because of the above- medulloblastoma and may lead to better mentioned reasons, they take on even more stratification systems. Other neurobiological significance in childhood. It has been well

86 Report of the Brain Tumor Progress Review Group documented that young children with brain relative infrequency of any individual tumor tumors, independent of the form of treatment type, the presence of embryonal/primitive they receive, have significant neurological tumors that often disseminate to the and cognitive sequelae. Furthermore, for leptomeninges, and the lack of interest in, older children and adolescents, treatment focus on, and funding for research on these may result in permanent long-term sequelae, primitive tumors. Specific challenges especially neurocognitive difficulties. Other associated with improving outcomes for common sequelae include endocrinological children with pediatric brain tumors and dysfunction, focal neurological deficits, and barriers to meeting these challenges are psychosocial sequelae. grouped below into four categories: Tumor Biology, Epidemiology, Treatment, and In a recent retrospective questionnaire Long-Term Sequelae. review of 1,845 children with brain tumors who survived for at least 5 years, it was TUMOR BIOLOGY noted that seizures, convulsions, or blackouts occurred in 28% of survivors; Challenges headaches, including migraines, were a problem in 37% of patients; and motor • Improved understanding of the genetic disabilities, such as balance problems, and environmental factors involved in weakness of the arms of legs, or tremors, the development of childhood CNS were noted in over 50% of children. A tumors sizeable minority of patients had blindness • Increased understanding of the cellular in one or both eyes, double vision, hearing origin of different types of pediatric loss, or persistent tinnitus. Over 50% of brain tumors those surviving for 5 years from the date of • Greater insight into the relationship diagnosis of their childhood brain tumors between normal brain development and required special education or learning- the neurogenetic/biologic disabled classroom settings, including 70% underpinnings of childhood nervous of those less than 3 years of age and 62% of system tumors those between 3 and 9 years of age. The • Determination of factors responsible incidence of secondary brain tumors in long- for the proclivity of some childhood term survivors of childhood brain tumors is brain tumors to disseminate within the rising, and second malignancies are almost nervous system early in the course of always fatal for this patient population. illness These sobering numbers highlight the • Clarification of the relationship problems faced by survivors of childhood between age, development, and brain tumors and the need for further outcome of childhood brain tumors research into means to reduce long-term • Enhanced understanding of the sequelae and remediate such problems when biologic differences between childhood they arise. and adult gliomas and the development of treatment approaches that take CHALLENGES AND QUESTIONS advantage of such differences • Better understanding of the On the largest scale, the overriding neurobiology of childhood primitive challenge for research into pediatric brain neuroectodermal tumors (including tumors is to improve outcome for children medulloblastoma) and other less with a host of different types of brain common embryonal tumors tumors. The predominant barriers are the

Pediatric Brain Tumors 87 • Development of better animal models EPIDEMIOLOGY that mimic human pediatric brain tumors, including those primarily Challenges occurring in children, such as PNETs • Creation of a biologically-based and other rarer pediatric tumors (e.g., classification of childhood brain atypical teratoid tumors) tumors that integrates molecular • Definition of relevant molecular aspects, neurobiological parameters markers for the prognosis of the and other neurodiagnostic findings diverse forms of childhood brain • Determination of the incidence of tumors individual types of childhood brain tumors, including low grade Barriers neoplasms, congenital tumors, and embryonal neoplasms • Insufficient appreciation of the important distinction between research Barriers required for childhood brain tumors and research required for adult tumors • Variability in the classification of rare • Lack of emphasis placed on the childhood brain tumors, especially defining biologic differences between congenital and embryonal lesions histologically identical tumors • Lack of methods to study individual occurring in children and adults, tumor types that occur less commonly especially the low- and high-grade • New coding of low-grade gliomas as gliomas “benign” tumors, which could increase • Paucity of investigations focused on the likelihood that children with these the molecular, genetic, and biologic diagnoses will not be included in aspects of embryonal childhood brain cancer registries tumors, including primitive • Lack of funding for epidemiological neuroectodermal tumors research, especially for the less • Lack of understanding of the common, but critically important, relationship between normal brain childhood brain tumor subtypes development and aberrations of such development in the etiology of TREATMENT childhood brain tumors • Lack of understanding of the Challenges uniqueness of the rarer childhood brain tumors; their overall importance, in • Development of more effective total; and the need to study these types treatments for childhood low- and of neoplasms individually high-grade gliomas • Lack of usable surrogate markers to • Development of more effective and determine the prognosis of childhood safer treatment approaches for brain tumors and to evaluate the childhood embryonal and primitive potential efficacy of agents used to tumors treat such 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 neurobiological/genetic characteristics biologically-based treatments for that underlie the variable severity of childhood brain tumors neurologic compromise in an individual child Barriers • Development of new strategies to prevent, ameliorate and remediate • Reluctance of industry to focus on neurocognitive and psychosocial developing drugs for pediatric brain sequelae of childhood brain tumors and tumors because of the relative rarity of their treatment childhood brain tumors • Evaluation of the impact of innovative • Difficulty in performing clinical trials biologically-based therapies on the for specific brain tumor subtypes developing nervous system because of the relative infrequency of • Research into factors involved in the specific types of childhood brain development of secondary tumors in tumors long-term survivors of pediatric brain • Insufficient development of novel tumors and more effective means to therapeutics designed for childhood treat such secondary malignancies. brain tumors such as primitive • Research into the effects of the neuroectodermal tumors diagnosis of a brain tumor on the • Hesitancy to apply new therapies early family unit, especially parental in their development, especially relationships and the impact on other biologically-based treatments, to children in the family childhood brain tumors • Paucity of research into the impact of Barriers new neurobiological treatments, such as anti-growth factor agents and anti- • Lack of appreciation of the severe angiogenesis agents, on the developing long-term sequelae suffered by nervous system children who have brain tumors, either • Limited scope of research focused on due to their tumor or its treatment the immunocompetence of children • Lack of emphasis on the psychosocial with brain tumors and the potential sequelae of these tumors on the child utility of different immunotherapeutic and the family approaches for children with brain • Lack of information concerning the tumors development and treatment of second malignancies in childhood brain tumor LONG-TERM SEQUELAE survivors • Lack of neuro-investigative techniques Challenges which take into account the developing nervous system and the differences • Detection of long-term neurologic, required in evaluation between adults cognitive, endocrinologic, systemic and children 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

Pediatric Brain Tumors 89 RESEARCH AND SCIENTIFIC of the short- and long-term effects of such PRIORITIES agents on the child and on the developing nervous system. Priority 1: RESOURCES NEEDED Understand the signaling systems involved in mitogenesis, survival, and cell • Tumor banking of pediatric brain death for pediatric tumors. tumor tissues • DNA microarrays applicable to • Understand how these signaling pediatric brain tumors and nervous systems relate to those in system development developmental neurobiology • Tissue arrays for pediatric CNS tumors • Use this understanding to identify new • Development of in vitro model systems targets for pediatric brain tumor for pediatric brain tumors therapy. • Animal model systems for pediatric brain tumors Priority 2: • Greater availability of well- characterized and validated clones or Fully characterize the phenotypic and lines of stem cells genetic alterations that are unique to • Imaging techniques for identifying benign and malignant pediatric brain tumors in situ for animal models of tumors. pediatric tumors • Coordinated effort, on a national basis, • Develop novel in vitro and animal of core facilities or coordinated models that faithfully recapitulate the individual laboratories with specific biology of these tumors. expertise and models (both academic • Use these models for the identification and private industry) to facilitate the and prioritization of targeted development of new drugs, biological therapeutic strategies for pediatric agents, or other treatment approaches brain tumors. • Funding for neuropsychological testing • Validated, user-friendly, pediatric Priority 3: instrument for measuring quality of life • Development of neuroimaging Investigate in detail the impact of the techniques that correlate with tumor and its treatment on long-term subclinical and clinical neurotoxicity. 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)

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

Participant Roster

David N. Louis, M.D. Jerome B. Posner, M.D. Massachusetts General Hospital Memorial Sloan-Kettering Cancer Center Co-Chair Co-Chair

Thomas Jacobs, Ph.D. Richard Kaplan, M.D. National Institute of Neurological National Cancer Institute Disorders and Stroke Executive Director Executive Director

Francis Ali-Osman, D.Sc. John Mazziotta, M.D., Ph.D. M.D. Anderson Cancer Center University of California - Los Angeles

Darell D. Bigner, M.D., Ph.D. Christina Meyers, Ph.D. Duke University M.D. Anderson Cancer Center

Keith L. Black, M.D., Ph.D. Robert H. Miller, Ph.D. Cedars-Sinai Medical Center Case Western Reserve University

J. Gregory Cairncross, M.D. Donna Neuberg, Sc.D. London (Ontario) Regional Cancer Center Dana-Farber Cancer Institute

Webster Cavenee, Ph.D. Cherie Nichols, M.B.A. Ludwig Institute for Cancer Research National Cancer Institute

Faith G. Davis, Ph.D. Roger Packer, M.D. University of Illinois-Chicago Children’s National Medical Center

Howard Fine, M.D. William M. Pardridge, M.D. National Cancer Institute University of California - Los Angeles

James E. Goldman, M.D., Ph.D. Dennis C. Shrieve, M.D., Ph.D. Columbia University University of Arkansas for Medical Sciences

Peter T.C. Ho, M.D., Ph.D. Robert Strausberg, Ph.D. Dupont Pharmaceuticals National Cancer Institute

Bertrand Liang, M.D. Susan L. Weiner, Ph.D. Amgen, Inc. Brain Tumor Coalition

Robert L. Martuza, M.D. Massachusetts General Hospital

BTPRG Roster 91 Brain Tumor Progress Review Group Roundtable Meeting

July 5–7, 2000

PARTICIPANT ROSTER

Francis Ali-Osman, D.Sc. James M. Boyett, Ph.D. University of Texas M.D. Anderson Cancer St. Jude Children’s Research Hospital Center Pim Brouwers, Ph.D. David M. Ashley, Ph.D., F.R.A.C.P. Baylor College of Medicine Royal Children’s Hospital of Parkville Melbourne, Australia Greta Bunin, Ph.D. Children’s Hospital of Philadelphia Toby Behar, Ph.D. National Institute of Neurological Disorders Peter C. Burger, M.D. and Stroke Johns Hopkins University

Michael E. Berens, Ph.D. J. Gregory Cairncross, M.D. Barrow Neurological Institute London (Ontario) Regional Cancer Centre Phoenix, AZ Kevin M. Callahan, Ph.D. Mitchel Berger, M.D. National Cancer Institute University of California, San Francisco Webster K. Cavenee, Ph.D. Rebecca Betensky, Ph.D. University of California, San Diego Harvard School of Public Health Antonio E. Chiocca, M.D., Ph.D. Jaclyn Biegel, Ph.D. Massachusetts General Hospital Children’s Hospital of Philadelphia University of Pennsylvania School of C. Norman Coleman, M.D. Medicine National Cancer Institute

Darell D. Bigner, M.D., Ph.D. R. Edward Coleman, M.D. Duke University Medical Center Duke University Medical Center

Keith L. Black, M.D. Tom Curran, Ph.D. Maxine Dunitz Neurosurgical Institute St. Jude Children’s Research Hospital Cedars-Sinai Medical Center Faith Davis, Ph.D. Peter M. Black, M.D., Ph.D. University of Illinois Brigham and Women’s Hospital Lisa M. DeAngelis, M.D. Ronald G. Blasberg, M.D. Memorial Sloan-Kettering Cancer Center 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. James F. Gusella, Ph.D. University of Ontario Massachusetts General Hospital

Ronald A. DePinho, M.D. Daphne A. Haas-Kogan, M.D. Dana-Farber Cancer Institute University of California, San Francisco

Glenn Dranoff, M.D. Terri Hallquist, M.S. Dana-Farber Cancer Institute National Cancer Institute

Lester R. Drewes, Ph.D. Alison L. Hannah, M.B.B.S. University of Minnesota, Duluth Sugen, Inc.

David Eckstein, Ph.D. Peter T.C. Ho, M.D., Ph.D. National Institute of Neurological Disorders DuPont Pharmaceuticals Company and Stroke Fred Hochberg, M.D. Howard Fine, M.D. Massachusetts General Hospital National Cancer Institute Susan Hockfield, Ph.D. Richard Fishel, Ph.D. Yale University Thomas Jefferson University John M. Hoffman, M.D. Henry S. Friedman, M.D. National Cancer Institute Duke University Medical Center Eric C. Holland, M.D., Ph.D. Brian Fuller, M.D. University of Texas M.D. Anderson Cancer National Cancer Institute Center

Candece L. Gladson, M.D. Peter D. Inskip, Sc.D. University of Alabama at Birmingham National Cancer Institute

Joseph C. Glorioso, Ph.D. Mark A. Israel, M.D. University of Pittsburgh School of Medicine University of California, San Francisco

James E. Goldman, M.D., Ph.D. Thomas P. Jacobs, Ph.D. Columbia University National Institute of Neurological Disorders and Stroke Ramon Gilberto Gonzalez, M.D., Ph.D. Massachusetts General Hospital C. David James, Ph.D. Mayo Clinic Cancer Center Rashmi Gopal-Srivastava, Ph.D. National Cancer Institute William G. Kaelin, M.D. Dana-Farber Cancer Institute Stuart A. Grossman, M.D. Howard Hughes Medical Institute Johns Hopkins University Harvard Medical School

Roundtable Roster 93 David Kaplan, Ph.D. David N. Louis, M.D. Montreal Neurological Institute Massachusetts General Hospital McGill University Marla B. Luskin, Ph.D. Richard S. Kaplan, M.D., F.A.C.P. Emory University School of Medicine National Cancer Institute Craig Lustig, M.P.A. Bruce Korf, M.D., Ph.D. Children’s Brain Tumor Foundation Partners Center for Human Genetics Lorraine Marin, M.D. Kenneth A. Krohn, Ph.D. Preuss Foundation for Brain Tumor University of Washington Medical Center Research

Carol Kruchko Robert L. Martuza, M.D. Central Brain Tumor Registry of the United Massachusetts General Hospital States John C. Mazziotta, M.D., Ph.D. Larry E. Kun, M.D. University of California, Los Angeles St. Jude Children’s Research Hospital Minesh P. Mehta, M.D. Andreas Kurtz, Ph.D. University of Wisconsin Massachusetts General Hospital Madison Medical School

Kathleen R. Lamborn, Ph.D. Ravi S. Menon, Ph.D. University of California, San Francisco Roberts Research Institute

Lois A. Lampson, Ph.D. Christina A. Meyers, Ph.D. Brigham and Women’s Hospital University of Texas M.D. Anderson Cancer Harvard Medical School Center

Frederick F. Lang, M.D. Judy Mietz, Ph.D. University of Texas M.D. Anderson National Cancer Institute Cancer Center Robert H. Miller, Ph.D. Anna T. Levy, M.S. Case Western Reserve University School of National Cancer Institute Medicine

Bertrand C. Liang, M.D. Sherie Morrison, Ph.D. Amgen, Inc. University of California, Los Angeles

Linda M. Liau, M.D., Ph.D. Raymond K. Mulhern, Ph.D. University of California, Los Angeles St. Jude Children’s Research Hospital School of Medicine Kate Nagy, M.A. Jay S. Loeffler, M.D. National Cancer Institute Massachusetts General Hospital

94 Report of the Brain Tumor Progress Review Group Maiken Nedergaard, M.D., Ph.D. Scott L. Pomeroy, M.D., Ph.D. New York Medical College Boston Children’s Hospital

Sarah J. Nelson, Ph.D. Jerome B. Posner, M.D. University of California, San Francisco Memorial Sloan-Kettering Cancer Center

Donna Neuberg, Sc.D. Vernon G. Pursel, Ph.D. Dana-Farber Cancer Institute U.S. Department of Agriculture

Edward A. Neuwelt, M.D. Samuel Rabkin, Ph.D. Oregon Health Sciences University Massachusetts General Hospital

Cherie Nichols, M.B.A. David B. Ramsay, M.D. National Cancer Institute London Health Sciences Centre

Judith Ochs, M.D. Richard M. Ransohoff, M.D. AstraZeneca Pharmaceuticals, Inc. Cleveland Clinic Foundation

Edward H. Oldfield, M.D. Jasti S. Rao, Ph.D. National Institute of Neurological Disorders University of Texas M.D. Anderson Cancer and Stroke Center

Roger I. Packer, M.D. Sandra A. Rempel, Ph.D. Children’s National Medical Center Henry Ford Hospital, Detroit

Luis Parada, Ph.D. Lynn Ries, M.S. University of TexasSouthwestern Medical National Cancer Institute Center at Dallas Gregory Riggins, M.D., Ph.D. William M. Pardridge, M.D. Duke University Medical Center University of California, Los Angeles School of Medicine Lucy B. Roarke, M.D. Children’s Hospital of Philadelphia David R. Parkinson, M.D. University of Pennsylvania

Roy A. Patchell, M.D. Bruce R. Rosen, M.D., Ph.D. University of Kentucky Massachusetts General Hospital

Audrey S. Penn, M.D. Steven Rosenfeld, M.D., Ph.D. National Institute of Neurological Disorders University of Alabama at Birmingham and Stroke Susan C. Rossi, Ph.D., M.P.H. Lawrence Pizzi, M.A. National Cancer Institute North American Brain Tumor Coalition Tom Roszman, Ph.D. Ian F. Pollack, M.D. University of Kentucky Medical Center Children’s Hospital of Pittsburgh

Roundtable Roster 95 David Rowitch, M.D., Ph.D. Michael D. Walker, M.D. Dana-Farber Cancer Institute National Institute of Neurological Disorders Harvard Medical School and Stroke

James T. Rutka, M.D., Ph.D., F.R.C.S.C. Jeannine Walston The Hospital for Sick Children, Toronto National Coalition for Cancer Survivorship

John H. Sampson, M.D., Ph.D. Susan L. Weiner, Ph.D. Duke University Medical Center North American Brain Tumor Coalition

Gail Segal Carol J. Wikstrand, Ph.D. North American Brain Tumor Coalition Duke University Medical Center American Brain Tumor Association Albert Wong, M.D. Dennis Shrieve, M.D., Ph.D. Kimmel Cancer Center University of Arkansas for Medical Sciences Thomas Jefferson University

Malcolm A. Smith, M.D., Ph.D. Roy S. Wu, Ph.D. National Cancer Institute National Cancer Institute

Evan Y. Snyder, M.D., Ph.D. Mark Yarborough, Ph.D. Boston Children’s Hospital University of Colorado Health Sciences Harvard Medical School Center

Harald W. Sontheimer, Ph.D. Richard J. Youle, Ph.D. University of Alabama at Birmingham National Institute of Neurological Disorders and Stroke Elizabeth Stevenson North America Brain Tumor Coalition Jeanne Young The Childhood Brain Tumor Foundation Philip J. Tofilon, Ph.D. University of Texas M.D. Anderson Cancer John S. Yu, M.D. Center Maxine Dunitz Neurosurgical Institute Cedars-Sinai Medical Center Arthur W. Toga, Ph.D. University of California, Los Angeles W.K. Alfred Yung, M.D. School of Medicine University of Texas M.D. Anderson Cancer Center 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

96 Report of the Brain Tumor Progress Review Group NIH Publication Number 01–4902 November 2000 T491