Pediatric Brain Tumor Foundation Institute at UCSF
Program Summary
The Pediatric Brain Tumor Foundation of the United States, based in Asheville, North Carolina, has awarded the UCSF Pediatric Brain Tumor Center a 3-year Institute Award for pediatric brain tumor research. 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.
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: J. Graeme Hodgson 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.