Pediatric Brain Tumor Foundation Institute at UCSF
Program Summary
The Pediatric Brain Tumor Foundation (PBTF) has established a world-class research institute at UCSF to define the poorly understood basic biology of several types of childhood brain tumors and improve therapies. As the largest non-governmental source of funding for childhood brain tumor research, the PBTF is dedicated to eradicating childhood brain tumors through supporting medical research, increasing public awareness, and providing educational and emotional support to children and families. The PBTF, based in Asheville, North Carolina, also supports research institutes at Duke University and The Hospital for Sick Children in Toronto.
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 of the PBTF Institute at UCSF focuses on medulloblastoma and brainstem glioma - alternately the most common and least treatable types of pediatric brain tumors.
Project Summaries
Project 1: Central Nervous System Development and Brain Stem Glioma Tumorigenesis
Principal Investigators: David H. Rowitch MD, PhD and Arturo Alvarez-Buylla PhD
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 stem. Correlating these findings with progneitor cells in the rodent brainstem will allow us to identify potential markers of germinal centers. Or final aim is to validate target gene/protein expression in rodent and human brainstem tissue. Identifying molecular features of these tumors should allow the selection of therapeutic agents that are tailored for this tumor type. Any new agent that is based upon the biologic features of the tumor should offer an improved prognosis for the patient.
Project 2: MYCN and Medulloblastoma Tumorigenesis
Principal Investigator: William A. Weiss MD, PhD
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. An emerging family of PI-3 kinase inhibitors has shown strong activity against Mycn and a much lower toxicity profile. This project will test PI3-kinase inhibitors in a transgenic mouse model of medulloblastoma to derive preclinical data of its effects.
Project 3: Genome-based Marker and Therapy Development in Pediatric Brain Tumors
Principal Investigators: C. David James PhD and Nalin Gupta MD, PhD
MicroRNAs have recently emerged as important regulators of stem cell differentiation and tumorigenesis. The long-term objective of this project is to develop and test microRNA-based therapeutic strategies for the treatment of pediatric brain tumors. In this proposal, the therapeutic potential of miRNA-124 for pediatric brainstem glioblastoma treatment will be assessed. Importantly, the reagents and methodologies developed through this work should be broadly applicable to all pediatric brain tumor types. Therefore, our studies, if successful, may have broad implications for incorporation of entirely novel treatment strategies for pediatric brain tumors with current standard-of-care therapies. We are also planning to use a number of new delivery strategies that permit much higher drug concentrations to be achieved in the CNS. These will include convection enhanced delivery (CED) and intranasal delivery (IND). We have shown that both CED and IND can achieve significant antitumor response in rodent tumor models. We plan to use these techniques to specifically deliver small inhibitory RNA molecules selected against genetic targets expressed in pediatric gliomas. Successful delivery of RNA molecules to tumors within the brain should open an entirely new avenue of drugs tailored for specific kinds of brain tumors. Using delivery directly to the brain should also reduce side effects of agents delivered orally or by the intravenous route.
Tissue Bank & Animal Core
Principal Investigator: C. David James PhD
The Tissue Bank at UCSF has several thousand brain tumor speciments and several hundred pediatric brain tumor specimens. Detailed analyses of these specimens identifies genetic clues that may explain their origin. When new targets have been identified and therapies developed, reliable animal models are critical for testing response to therapy prior to clinical trials in humans. The UCSF Animal Core, led by Dr. David James, uses transplantable xenograft, allograft, and isograft tumor models in support of pediatric brain tumor translational research.