Research grants funded in 2006
Basic and Translation Research Grants: $50,000 annually
Cornell University, Convection-enhanced delivery of recombinant immunotoxin 8H9-PE38 for the treatment of pediatric infiltrative brainstem tumors, Mark Souweidane, M.D.
A particular type of childhood brain tumor that occurs in the brain stem, the pontine glioma, is invariably fatal. Treatment is limited only to radiation therapy as a means to slowing tumor growth. Reasons for this trouble include the in ability to safely remove them, difficulty with therapeutic drugs gaining access to the involved tissue, side effects of treatment, and lack of specificity of anti-cancer drugs. Our study addresses these issues by combining two recent developments in cancer therapy: local infusion and recombinant immunotoxins.Local infusion delivers the agent through small catheters placed directly into the tissue. This approach avoids toxicity to other organs and achieves high local drug concentrations. Molecules that possess a high degree of specificity against tumor cells have been designed. Monoclonal antibodies (MAbs) are such molecules. They can be attached (conjugated) to a toxin that kills cells and delivered locally to the brain. Our study aims to define the smallest infusion dose of the conjugated molecule for the brain stem and determine the anti-tumor effect of the drug. Human brain tumor tissue will be implanted in a model system and treated locally with the agent. The resulting data will help design and implement clinical studies for children with malignant brain stem tumors.
Duke University Medical Center, Elimination of pediatric brain tumors through activation of the apoptosome, Sally Kornbluth, Ph.D.
Pediatric brain tumors are the leading cause of cancer-related death in children. The clinical management of these cancers is complicated by radiotherapy-induced neurological impairment and the development of chemotherapeutic resistance. To circumvent these limitations, the ideal treatment would target the destruction of brain cancer cells while sparing the surrounding normal tissue. In studying an innate program of cellular suicide, termed apoptosis, we recently discovered a potential mechanism for selectively inducing cell death in pediatric brain tumors. Normally, apoptosis is initiated when a cell, sensing irreversible damage, triggers a signaling pathway that ultimate leads to its death. However, many cancers, including pediatric brain cancers, have developed mechanisms that block the initial steps of this pathway. Although pediatric brain cancer cells are resistant to initiation of the death program, we recently found that they are remarkably susceptible to apoptosis induced by a protein active further along the cell death pathway. Importantly, normal neural tissue is highly resistant to this same protein. The differential sensitivity provides a potential method for inducing death in cancerous cells while leaving normal tissue unharmed. The current proposal is centered on exploiting this phenomenon in order to develop novel therapies for the treatment of pediatric brain cancers.
Memorial Sloan-Kettering Cancer Center, Multi-drug resistance to phenotype of the side population in medulloblastoma models, Eric Holland, M.D., Ph.D.
Medulloblastoma is the most common childhood brain tumor. Current therapies resulted in a 70 percent survival rate, but with severe side effects. Ongoing research into the origin and mechanisms of brain tumor development promised to provide additional treatment options with a lower degree of toxicity. In normal brains a specific class of cells, called stem cells, have the capacity to renew and generate all the component of the brain. Interestingly, recent studies have demonstrated the presence of stem cells inside the tumors. Furthermore, while most tumor cells are killed during therapy, the stem cells persist and can repopulate the tumors once treatment has ended. We now have evidence that this phenomenon results from the ability of stem cells to exclude drugs from their internal environment. Our laboratory has developed models for pediatric brain cancer in humans and we aim to elucidate the mechanism(s) leading to drug resistance in these tumors. We suspect that the presence of cancer stem cells within these tumors leads directly to their drug resistance. The results of our studies should aid considerably in the development of new strategies to render cancer stem cells more responsive to treatment.
Memorial Sloan-Kettering Cancer Center, Translation regulation by TXC2 in normal cerebellum and medulloblastoma, Anna Marie Kenney, Ph.D.
Medulloblastomas arise in young children in a part of the brain called the cerebellum. Immature neural cells in the cerebellum divide rapidly in mice and humans soon after birth. These cells are proposed cells of origin for certain classes of medulloblastoma. Current treatments for medulloblastoma do not distinguish between tumor cells and normal cells in the still-developing brain, leaving patients with devastating, life-long side effects. Understanding events controlling immature neural cells proliferation will yield insight into how they may become transformed into medulloblastoma. We can then develop treatments that specifically attack the tumor cells, by targeting molecules that are inappropriately active. My research focuses on using neural cells cultures and mice that develop medulloblastomas to identify ways that making new proteins inside cells promotes precursor proliferation in the cerebellum and in medulloblastomas. New proteins need to be made in order for cells to increase in size and divide. The molecules that generate new protein are essential for immature cerebellar neural cell division and survival, and their activity is increased in medulloblastoma. In the future, we will use model systems of brain tumors similar to those children suffer, to screen protein synthesis-blocking drugs for their effectiveness against medulloblastomas.
Stanford University, Identification of medulloblastoma tumor stem cells using self-renewal pathways, Irving Weissman, M.D., Ph.D., and Michael Edwards, M.D.
Medullablastoma is the most common malignant pediatric brain tumor. Children with this form of cancer receive a combination of treatments, involving surgery, chemotherapy and radiation. These treatments are associated with long-term risks of cognitive dysfunction and developmental abnormalities. The development of more efficient and specific therapies will depend on our understanding of the mechanisms involved with cancerous growth of brain cells. Our hypothesis is that within medullablastomas, only a small group of cancer stem cells retain the ability to initiate and replicate the tumor. These tumor cells are the most dangerous because only they are responsible for growth, metastasis and the recurrence of the cancer. Our goal is to isolate cancer stem cells for medulloblastoma based on an approach of selecting tumor cells that demonstrate special biochemical activities indicative of growth. We have developed the means to measure the activity level of two biochemical pathways that are associated with cell self-renewal and that are known to be altered in medulloblastoma. If our study links these biochemical activities to the growth of cancer stem cells in medulloblastoma, then new therapies can be developed to eliminate this cell population, thereby improving the outcome and survival of children affected by this disease.
"Nicki White Memorial Grant Award" awarded in memory of Nicki White
Washington University School of Medicine, Modulation of intracranial brain tumor growth and therapeutic responses by cAMP, Joshua Rubin, M.D., Ph.D., For those who care for children with brain tumors, the desperate need for better treatment is obvious. Currently, hope is placed on the power of genomics and biologically based therapies to advance pediatric brain tumor care. The promise of this approach, however, has not been realized and it is important to question whether there are missing elements in the approach. We study the role that the developing brain plays in the genesis of pediatric brain tumors. We found the brain-derived growth factor CXCL12 regulates the growth state of tumor cells by controlling the level of a growth inhibitory molecule known as cyclic AMP (cAMP). In the growing brain, CXCL12 lowers cAMP levels, which permits the dysregulated growth of tumor cells. Consistent with this, analyses alone may not predict the growth potential of a tumor and that cAMP elevating therapies may provide an improvement in brain tumor outcome. Here, we propose to better define the role of cAMP and the activity of cAMP-elevating drugs in brain tumors. This will advance our understanding of brain tumor biology and bring cAMP-elevating drugs to clinical trial for brain tumors.
Pediatric Brain Tumor Foundation Institute Awards:
$1,000,000 annually for six years
Pediatric Brain Tumor Foundation Institute at Duke University, Director: Darell Bigner, M.D., Ph.D.
- Project 1: Establishment of Cell Lines, Xenografts and Monoclonal Antibodies, Darell Bigner, M.D., Ph.D.
- Project 2: Serial Analysis of Gene Expression of Childhood Brain Tumors, Hai Yan, M.D., Ph.D.
- Project 3: Altered Signal Transduction, Pathways and Small Molecule Inhibitors, Jeremy Rich, M.D.
- Project 4: Gene and Radiotherapy, Michael Zalutsky, Ph.D.
- Project 5: Definition of Non-AGT/DNA Mismatch Repair Deficiency Mechanisms of Resistance to Temozolomide, Henry Friedman, M.D.
- Project 6: Fibro Growth Factor as a Therapy for Medulloblastoma, Rob Wechsler-Reya, Ph.D.
- Project 7: Investigational New Drug and Reagent Preparation Core, Michael Granger, Ph.D.
- Project 8: Tissue Bank Core, Roger McLendon, M.D.
- Project 9: Pilot Project Core, Darell Bigner, M.D., Ph.D.
Pediatric Brian Tumor Foundation Pre-Insitute Awards:
$100,000 annually for three years
University of San Francisco, Program on Pediatric Brain Tumor Biology and Therapeutics, Mitchel Berger, M.D., Principal Investigator.
- Project 1: Central Nervous System Development and Brain Stem Glioma Tumorigenesis, David Rowitch M.D., Ph.D., and Arturo Alverez-Buylla, Ph.D.
- Project 2: Pediatric Brain Tumor Xenograft Panel, David James, Ph.D.
- Project 3: MYCN and Medulloblastoma Tumorigenesis, William Weiss, M.D., Ph.D.
- Project 4: Genome-based Marker and Therapy Development in Pediatric Brain Tumors, Graeme Hodgson, Ph.D.
- Project 5: Convection-enhanced and Intra-nasal Delivery of Therapeutic Agents, Natlin Gupta, M.D., PH.D.
- Project 6: Administrative and Statistical Core, Mitchel Berger, M.D.
- Project 7: Tissue Bank and Neuropathology Core, Scott VandenBerg, M.D., Ph.D.
Childrens Hospital Los Angeles, Biology and Therapy of Pediatric Brain Tumors: Saving Lives, Saving Neurons, Robert Seeger, M.D., Principal Investigator.
- Project 1: Genomics, Robert Seeger, M.D.
- Project 2: Microenvironment and Angiogenesis, Anat Erdreich-Epstein, M.D., Ph.D.
- Project 3: Immunotherapy, Leonid Metelitsa, MD, Ph.D.
- Project 4: Experimental Therapeutics, Patrick Reynolds, M.D. Ph.D.
- Project 5: Molecular Imaging, Stefan Blumi, Ph.D.
- Core 1: Pathology, tissue banking and cell lines, Floyd Giles, M.D.
- Core 2: Pediatric Brain Tumor Core, Anat Erdreich-Epstein, M.D., PhD.
- Core 3: Imaging, Mike Rosol, Ph.D.
- Core 4: Biostatistics, Richard Sposto, Ph.D.
Hospital for Sick Children, James Rutka, M.D., Ph.D., Principal Investigator.
- Project 1: Identification of Interstitial Germline Deletions in Children with Complex Clinical Syndromes that Include Medulloblastoma, Michael Taylor, M.D., Ph.D, Eric Bouffet, M.D.
- Project 2: High Resolution Genotyping of a Large Cohort of Pediatric Medulloblastomas
- Michael Taylor, M.D., Stephen Scherer, Ph.D., James Rutka, M.D., Ph.D.
- Project 3: Ultrahigh Resolution Genotyping of Highly Purified Medulloblastoma, Peter Dirks, M.D., Ph.D.
- Project 4: Identification of Truncating Mutations in Pediatric Medulloblastoma, Peter Dirks, M.D., Ph.D., James Rutka, M.D., Ph.D., Michael Taylor, M.D., Ph.D.
