Summary of Activities
Project 1. Systematic Oncogenic Profiling of Pediatric Astrocytoma
Project Leader: Hai Yan, M.D., Ph.D., Professor of Pathology
Goals: To perform a genome-wide, high-resolution measurement of the genomic content changes in pediatric gliomas and to determine the oncogenic roles of the identified genes in pediatric glioma pathogenesis; and to identify mutated genes associated with tumor initiation, growth, spread, or other glioma properties by conducting a genome-wide mutation analysis.
Project 2. Identifying Pathways Regulated by Medulloblastoma Tumor Suppressor MLL2
Project Leader: Yiping He, Ph.D., Assistant Professor of Pathology
Goals: To identify the medulloblastoma driving pathways that are dysregulated by MLL2 alterations, and to examine the primacy of MLL2 mutations in medulloblastoma genesis through in vivo studies.
Project 3. Characterization of the Genomic Alterations of Human Diffuse Intrinsic Pontine Glioma IDIPG) and the Development of Improved Mouse Models of DIPG
Project Leader: Oren J. Becher, M.D., Assistant Professor of Pediatrics
Goals: To develop improved mouse models of diffuse intrinsic pontine glioma, and to determine the frequency of PDGFRα mutations in human DIPGs and determine whether these mutations confer sensitivity to inhibitors of PDGFR signaling.
Project 4. Eliminating Brain Cancer Cells Through Apoptosome Activation
Project Leader: Sally A. Kornbluth, Ph.D., James B. Duke Professor of Pharmacology and Cancer Biology
Goals: To determine the optimal metabolic modulation/chemotherapeutic combination for treatment of pediatric brain tumors, to test these agents in animal models of pediatric brain tumors, and to test the effects of Wee1 modulation for therapy in pediatric brain tumors.
Project 5. Clinical Treatment of Pediatric Medulloblastoma Using Novel Small Molecular Inhibitors of Smoothened Activity: A Translational Approach
Project Leader: Wei Chen, P.D., Assistant Professor of Medicine
Goals: To perform lead compound optimization on promising Hedgehog/Smoothened inhibitors using known structure-activity relationships (SAR); to identify a molecular tumor signature associated with response to Smo inhibitors and conversely identify biomarkers that predict for resistance to the Smo inhibitors using medulloblastoma cell lines, mouse tumors, and brain tumor models including xenograft systems and Patched/flox mice; and to complete the requisite preclinical studies to file an Investigational New Drug (IND) application.
Project 6. Oncolytic Poliovirus Against Metastatic Medulloblastoma
Project Leader: Matthias Gromeier, M.D., Associate Professor of Surgery (Neurosurgery) and Molecular Genetics and Microbiology
Goals: To elucidate the role of mitogenic signal transduction to iIF4G in control of viral tumor cell killing, and to investigate PVS-RIPO oncolysis in primary explant medulloblastoma xenografts in vivo.
Project 7: Dendritic Cell Vaccines Targeting Medulloblastoma and Medulloblastoma Stem Cells
Project Leader: John H. Sampson, M.D., Ph.D., Dr. Robert H. Wilkins and Gloria Wilkins Professor of Neurosurgery
Goals: To amplify RNA from sorted human CD133+ MB BTSC and CD133-MB tumor cells and determine the capacity for DCs loaded with RNA libraries enriched for MB BTSC antigens to elicit cellular immune responses capable of preferentially killing CD133+ MB BRSC in vivo using a SCID/NOD mouse xenograft model, and to generate sufficient toxicity and efficacy data for IND application to the FDA for MB tumor RNA-loaded, DC-based vaccine approaches in children with high-risk MB, and to conduct a Phase I clinical trial.
Project 8. T Cell Adoptive Transfer Therapy for Recurrent Medulloblastoma
Project Leaders: Duane A. Mitchell, M.D., Ph.D., Assistant Professor of Surgery (Neurosurgery); Gerald A. Grant, M.D., Associate Professor of Pediatric Neurosurgery; John H. Sampson, M.D., Ph.D.
Goals: To investigate the capacity to expand antigen-specific T cells targeting survivin, CMVpp65 and IE1, and total tumor antigens using RNA-pulsed DCs generated from patients with reMB and mediate the killing of autologous tumor in vitro and matched xenografts in vivo; to conduct a Phase I clinical trial investigating the safety and immunologic effects of DC + xALT therapy using the most promising strategy deemed from Aim 1; and to determine the impact of induction therapy and HDC + PBSCT on circulating levels of homeostasis and inflammatory cytokines, toll-receptor activation status, and on the functional recovery of lymphocyte and NK cellular subsets in children with reMB receiving DC+ xALT.
Project 9. Targeted Radiotherapy of Medulloblastoma
Project Leader: Michael R. Zalutsky, Ph.D., Jonathan Spicehandler Professor of Neuro-oncology Research
Goals: To obtain the pharmacokinetics, toxicology, dosimetry and efficacy data required to obtain an IND to initiate the clinical evaluation of [177LU-DOTA0,Tyr3]octreotate (177Lu-DOTA-TATE) in patients with medulloblastomas; to develop octreotate analogues with prolonged 177Lu residence times in medulloblastoma cells by alterations in chelate charge and conformation and insertion of protease specific recognition sequences; to adapt radiosynthetic strategies originally developed for labeling internalizing antibodies for labeling octreotate analogues with the highly cytotoxic α-particle emitter 211At. If promising therapy results are obtained, radiolysis-resistant procedures will be developed for use at clinical relevant levels; and to evaluate the potential utility of promising 177Lu- and 211At-labeled peptides as targeted medulloblastoma radiotherapeutics.
Project 10. Specific Antigen-Targeted Immunotherapy of Medulloblastoma
Project Leaders: Darell D. Bigner, M.D., Edwin L. Jones, Jr. and Lucille Finch Jones Cancer Research Professor; Chien-Tsun Kuan, Ph.D., Assistant Professor of Pathology
Goals: To develop second generation, high affinity anti-SSTR2A reagents; to identify new MAbs against the medulloblastoma tumor antigens podoplanin, chondroitin sulfate proteoglycan, and gangliosides 3’-isoLM1 and 3’,6’-isoLD1; and to discover antigens on brain tumor stem cells and establish human brainstem xenograft models.
Core 1. Biorepository Core
Core Director: Roger E. McLendon, M.D., Professor of Pathology
Goals: To provide DNA, RNA, and tissue from neoplastic brain as well as DNA, RNA, tissue, and serum from normal blood, brain, and other body sites to investigators within the Institute, as well as qualified national and international researchers, in a manner in which they can be used for a variety of studies and techniques; and to apply an integrated tissue bank/clinical data informatics system that allows the rapid identification of patient groups based on common demographics, clinical data, tissue diagnoses, and/or imaging studies and the efficient management and analysis of data from research results and clinical outcome under the oversight of a Tissue Committee.
Core 2: Cell Lines and Xenografts Core
Core Directors: Darell D. Bigner, M.D., Ph.D.; Henry S. Friedman, M.D., James B. Powell, Jr. Professor of Neuro-oncology; Stephen Keir, Dr.P.H., Associate Professor of Surgery
Goals: To establish, in culture, stable pediatric brain tumor cell lines from a variety of tumor types, especially medulloblastomas, supratentorial PNETs, and grades III and IV astrocytomas; to establish human pediatric brain tumor xenograft mice models for various tumor types, especially medulloblastomas, supratentorial PNETs, and grades III and IV astrocytomas; and to make these lines and xenografts available to other researchers and institutions for research purposes.
Core 3. Administrative Core
Core Director: Darell D. Bigner, M.D., Ph.D.
Goals: To provide day-to-day administration of the PBTF Institute projects and cores; to administer the PBTFI Developmental Research and Career Development Programs; to provide scientific oversight and monitoring of the projects and cores; and to enhance research collaborations within the Institute, between the Institute and the other PBTF Institutes, the Duke University Medical Center, outside institutions, and the broader scientific community.
Developmental Research Program
Director: Darell D. Bigner, M.D., Ph.D.
Goal: To provide “seed” money to investigators who may be new to the field of pediatric brain tumor research or investigators who wish to pursue novel research in the field.
Career Development Program:
Director: Darell D. Bigner, M.D., Ph.D.
Goal: To provide start-up funds to young investigators who wish to pursue pediatric brain tumor research.
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