Brain Tumor Progress Review Group - Cancer Biology and Etiology

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

Participants: Michael Berens Mitchel Berger Webster Cavenee Rolando Del Maestro Ronald A. DePinho Richard A. Fishel Henry Friedman Candece Gladson

Peter T. C. Ho Susan Hockfield Mark A. Israel C. David James William G. Kaelin Robert L. Martuza Christina A. Meyers Jasti Rao

Sandra Rempel James Rutka Robert L. Strausberg Richard Vallee Jeannine Walston Albert Wong Roy S. Wu W. K. Alfred Yung

STATEMENT OF THE PROBLEM

• Brain tumors are highly heterogeneous, both phenotypically and genotypically.

• Significant gaps exist in our knowledge and understanding of the genes, genetic changes, and pathways involved in the genesis, progression, and biological and clinical behavior of brain tumors.

• There is currently an inadequate understanding of brain tumor biology, particularly as it relates to the complex environment of the brain.

• The achievement of significant advances in diagnosis, prognosis, therapy, and prevention of brain tumors will require unraveling and understanding the cellular and molecular biology of brain tumors and their interactions with normal brain.

CHALLENGES AND QUESTIONS

• What are the genetic changes and pathways of oncogenesis and progression that account for the heterogeneity of brain tumors, and how can these be studied?

• Which genes, genetic changes, and pathways are important to the initiation, maintenance, and progression of brain tumors?

• Are the genetic changes and pathways that are required for initiation the same as those required for maintenance of the neoplastic phenotype and its biological behavior?

• What model systems and approaches are required to advance our study of these multigenetic changes and pathways?

• What are the interactions between the brain tumor and the normal brain?

• How do tumor-brain interactions contribute to oncogenesis and metastasis in the central nervous system?

• "Seed-soil" interactions: How does the spatial-anatomical site of the tumor against its specific genetic background determine the gene expression patterns and contribute to tumor heterogeneity, biological and clinical behavior, and therapeutic outcome?

• Are there genetic changes and pathways that are common to different brain tumor subtypes?

• What pathways, such as signaling, apoptosis, cell cycle, and migration, are involved in the response of brain tumors to intra- and extracellular stimuli such as growth factors or redox changes?

• What are the stem cells and progenitor cells of the different brain tumor subtypes?

• What model systems and approaches are required to advance the study of brain tumor biology and of the interactions between tumor cells and normal brain?

• If the genetic changes or lesions that initiate cancer are different from those required for progression and maintenance, could these be targeted in order to develop novel therapies?

BARRIERS

• Interdisciplinary barriers:

-- There is poor communication and collaboration between researchers in neurobiology and those in neurooncology, although expertise and advances in each field are essential to advancing understanding of brain tumor biology.

-- Current infrastructure and systems do not encourage or facilitate interdisciplinary interaction.

-- In the current grant review process, interdisciplinary grants that would encourage collaboration are often not reviewed favorably because of the existing review criteria.

• Tissue resource barriers: Existing tumor banks often do not have appropriate, relevant information, such as information on diagnosis, biological characteristics, natural history, and therapeutic outcome. The banks also often do not collect normal tissue or blood.

• Models: There is a lack of appropriate in vitro and in vivo models and systems with which to study the complex biology of brain tumors.

• Technological barriers: There is an inadequate application to brain tumor biology research of the latest technological advances, such as those in genomics and proteomics, structural biology, chemical biology, and high-throughput screening strategies.

RESEARCH AND SCIENTIFIC PRIORITIES

Priority 1: Understand the complex biology of brain tumors and their interaction with the normal brain as it relates to oncogenesis, progression, and heterogeneity.

• Define the multigenetic changes and pathways involved in oncogenesis, progression, and maintenance of brain tumors, with particular attention to their heterogeneity.

• Identify the genes and pathways that are differentially involved in tumor initiation and maintenance.

• Characterize the interactions of the tumor cell with normal brain components as determinants of heterogeneity, gene expression, biological and clinical behavior, and therapeutic response within the context of the specific anatomical sites of the brain in which the tumor is located.

• Define and characterize the cells of origin of different brain tumor subtypes.

Priority 2: Develop appropriate model systems for studying brain tumor biology that will allow for the following:

• Mimic the biological complexity of the brain, including brain matrix

• Facilitate comparative genetic studies in human brain tumors and animal brain tumor models

• Provide an interface between tumor cell and stem cell biology

• Study interactions and pathways between brain tumor cells and cellular components of normal brain

• Study molecular, cellular, and spatial heterogeneity in brain tumors

• Study the functional outcome of specific genetic lesions

• Evaluate novel therapies that target specific genes, gene products, and pathways

Priority 3: Develop high-throughput approaches to understand gene function and to identify the targets and pathways that are critical to brain tumor biology and therapy.

RESOURCES NEEDED

Priority 1

• Addressing the complex biology of brain tumors requires innovative tumor banking and characterization facilities with relevant and appropriate databases. These facilities will enable the following:

-- Collect and bank tissue, blood, cerebrospinal fluid, and (when available) normal brain from patients with all varieties of brain tumors.

-- Maintain a comprehensive database of relevant clinical and demographic, pathological, biological, imaging, and therapeutic information on tumors.

-- Involve the multidisciplinary participation of surgeons, pathologists, scientists, and other professionals, including neurooncologists, for tissue processing.

-- Have mechanisms in place to ensure access by researchers to the material and data in the bank.

-- Include local (institutional) or regional centers and encourage communication and collaboration among centers.

-- Receive ongoing funding, specifically for longer than 5-year periods, because of the long-term nature of tissue banking

• Establish a centralized molecular profiling (cDNA and tissue array) resource with a strong bioinformatics component to profile gene expression patterns and genetic abnormalities in different brain tumor types. Such a facility could be located at NCI or NINDS or could be extramural.

• Develop the infrastructure and mechanisms to open up communication and collaboration among researchers in neuroscience, neurobiology, neurooncology, and cancer biology. Such an infrastructure would include:

-- Workshops and specialized meetings among these scientists

-- New funding mechanisms and grant review criteria appropriate for interdisciplinary research

Priority 2: Targeted funding is needed for the development of model systems.

Priority 3: Resources are needed to develop the following:

• Chemical and combinatorial libraries and high-throughput assays to 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