Program Summary: In 2006, the Department of Neurological Surgery at the UCSF, the Hospital for Sick Children in Toronto, and Children's Hospital of Los Angeles were awarded grants by the Pediatric Brain Tumor Foundation of the U.S. (PBTFUS) to establish Pediatric Brain Tumor Pre-Institutes. The biology of pediatric brain tumors is not as well understood as that of adult brain tumors, and as a result new therapies have been slow to develop. The research program funded by this grant aims to address this challenge and provide new treatments to children with brain tumors by using innovative, biologically based strategies. The program at UCSF consists of five main projects and two core facilities focused on pediatric brainstem glioma and medulloblastoma.
Principal Investigator: Mitchel S. Berger MD
Total Project Period: 04/01/06-03/31/09
Project 1: Central Nervous System Development and Brain Stem Glioma Tumorigenesis
Principal Investigator: David H. Rowitch MD, PhD and Arturo Alvarez-Buylla PhD
Project Summary: Pediatric brainstem glioma is a particularly aggressive type of brain tumor affecting children. Prognosis for patients is generally very poor because the location of the brainstem typically makes surgery impossible and these tumors are highly resistant to radiation or chemotherapy. This project explores the hypothesis that brainstem gliomas originate from neural stem cells or early progenitors within the brainstem. The first goal of the project is to characterize progenitor cells in the normal developing brain and the adult brain.
The second goal of the project is to determine the features of a specific class of proteins that are commonly overexpressed in both adult and pediatric brainstem gliomas. By defining similarities in the way the disease behaves in adults and children, we will gain a better understanding of how therapeutic strategies applied to adult brainstem gliomas could be meaningfully extended to pediatric brainstem gliomas.
Project 2: Pediatric Brain Tumor Xenograft Panel
Principal Investigator: C. David James PhD
Project Summary: The goal of this project is to develop and characterize a pediatric brain tumor xenograft panel for broad distribution and use in neuro-oncology research. There is great need for such a panel to be developed due to the relative lack of pediatric brain tumor models for use in marker and target identification, and corresponding preclinical testing of experimental therapeutics. We aim to develop as many as 20 serially transplantable pediatric brain tumor xenograft lines, each derived from distinct pediatric brain tumor patients, and sustained through subcutaneous growth in nude mice. We expect that results from testing anti-tumor therapeutics in this model will expedite the identification of effective therapies and lead to improved consistency of clinical trial results in patients.
Project 3: MYCN and Medulloblastoma Tumorigenesis
Principal Investigator: William A. Weiss MD, PhD
Project Summary: Medulloblastoma, primitive neuroectodermal tumors of the cerebellum, are the most common CNS malignancy in children. The uncontrolled growth of cells in medulloblastoma is largely due to an abnormal cell-signaling pathway that causes an accumulation of the Mycn protein. Mycn can be destabilized by small molecule inhibitors of the enzyme Phosphatidylinositol-3 (PI3)-kinase, but until recently these inhibitors have been too toxic for use in patients. A new PI-3 kinase inhibitor developed at UCSF has strong activity against Mycn and a much lower toxicity profile. This project will test the new inhibitor in a transgenic mouse model of medulloblastoma to derive preclinical data of its effects.
Project 4: Genome-based Marker and Therapy Development in Pediatric Brain Tumors
Principal Investigator: J. Graeme Hodgson PhD
Project Summary: The main goal of this project is to assess the therapeutic potential of controlling gene expression in pediatric brain tumors. There is evidence that some genes overexpress molecules that suppress apoptosis (cell death) in pediatric brain tumors. By targeting these genes with short-interfering RNA (siRNA), researchers hope to induce an apoptotic response. This project focuses on the siRNA-mediated down regulation of the apoptosis suppressor PVT1. Investigators hypothesize that this down regulation will block tumor growth in medulloblastoma xenografts in which PVT1 is amplified. To test this hypothesis, researchers are working to develop siRNA inhibitors of PVT1 and to identify new molecular targets for therapeutic intervention in pediatric brain tumors.
Project 5: Convection-enhanced and Intranasal Delivery of Therapeutic Agents to the Rodent Brainstem
Principal Investigators: Nalin Gupta MD, PhD and Krystof Bankiewicz MD, PhD
Systemic therapy for central nervous system tumors is limited by the inability to achieve high drug concentrations within the brain, regardless of the physical and chemical properties of he drug, or manipulations to increase capillary permeability. This project focuses on alternative methods of delivering drug directly to the brain tissue. Convection enhanced delivery. Intranasal delivery is another route that has shown to deliver effective concentrations of therapeutic agents in preclinical studies and is completely noninvasive. The specific aims of the project include 1) establishing and orthotopic intracranial tumor model in the rodent brainstem; and 2) comparing the volume of distribution and effectiveness of gadolinium- and CPT-11-loaded liposomes using CED and IND in an orthotopically established brainstem tumor model.
To contact the UCSF Department of Neurological Surgery with questions about medical matters, call 415-353-7500 or fax 415-353-2889.
For information about the UCSF Neurological Surgery Residency Program, call 415-353-3904 or fax 415-353-3907.
Copyright ©2003 UCSF Neurosurgery. All rights reserved.