Myc Signaling in Medulloblastomas
Principal Investigator: CHARLES GEORGE EBERHART
Abstract: Medulloblastomas, embryonal neoplasms arising in the cerebellum, are the most common malignant pediatric brain tumor. We propose several lines of investigation into the roles of c-Myc and N-Myc in medulloblastoma pathobiology. The primary investigator, Dr. Charles Eberhart, is a neuropathologist with a scientific background in Drosophila genetics, who plans a career as an independent clinician scientist researching brain tumors. To accomplish his goals he requires additional training in techniques commonly used to study tumors in the laboratory, including cell culture and mouse transgenic models. Pursuing the specific aims we propose will teach Dr. Eberhart these skills, and enable him to make the transition to an independent career in cancer research. Myc transcription factors are emerging as important modulators of medulloblastoma, biology. In Specific Aim 1 we investigate links between Myc levels in medulloblastoma specimens and clinical outcome. The effects of Myc are varied, and while several Myc targets have been isolated in fibroblasts and hematologic malignancies, it is likely that the profile of genes regulated by Myc will differ between tumor types. We therefore propose in Specific Aim 2 to identify c-Myc: targets in medulloblastoma cell lines by modulating c-Myc levels and evaluating the changes in gene expression profiles using microarrays. In Specific Aim 3 we confirm the clinical importance of these targets by analyzing their expression in medulloblastoma tumor samples with varying c-Myc levels. Finally, in Specific Aim 4 we propose developing a novel medulloblastoma transgenic model by overexpressing c-Myc in the cerebellum of transgenic mice.
Funding Period: 2002-05-01 - 2007-04-30
more information: NIH RePORT
- c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patientsAndre O Von Bueren
Neuro Oncology Program, University Children s Hospital, Zurich, Switzerland
BMC Cancer 11:74. 2011..To study whether and how c-MYC expression determines response to radio- and chemotherapy in childhood medulloblastoma (MB)...
- Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastomaYunqing Li
Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
Lab Invest 88:98-111. 2008..The findings provide a potential explanation for the high frequency of c-Myc overexpression in medulloblastoma and suggest a cooperative role for c-Met and c-Myc in large-cell anaplastic medulloblastoma formation...
- Hedgehog signaling promotes medulloblastoma survival via Bc/IIEli E Bar
Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross Building 558, Baltimore, MD 21205, USA
Am J Pathol 170:347-55. 2007..These data demonstrate that BclII is an important mediator of Hh activity in medulloblastoma and suggest new strategies for combined chemotherapeutic regimens...
- Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumorsXing Fan
Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
Cancer Res 66:7445-52. 2006..Stem-like cells in brain tumors thus seem to be selectively vulnerable to agents inhibiting the Notch pathway...
- Brief report: S6 ribosomal protein phosphorylation in autistic frontal cortex and cerebellum: a tissue array analysisCharles G Eberhart
Johns Hopkins University, Baltimore, MD, USA
J Autism Dev Disord 36:1131-5. 2006..However, no consistent alterations in S6 phosphorylation were detected in autistic tissues compared to controls in the brain regions analyzed...
- Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiationXiaohua Su
Department of Molecular Genetics, University of Texas M D Anderson Cancer Center, 1515 Holcombe Boulevard, Mail 1006, Room S13 8136C, Houston, TX 77030, USA
Mol Cell Biol 26:1666-78. 2006..Furthermore, these results suggest that such a mechanism plays a role in the formation of human medulloblastoma...
- c-myc overexpression causes anaplasia in medulloblastomaDuncan Stearns
Department of Neuropathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205, USA
Cancer Res 66:673-81. 2006..Because anaplastic changes are often observed in recurrent medulloblastoma, we propose that c-myc dysregulation is involved in the progression of these malignant embryonal neoplasms...
- Notch3 signaling initiates choroid plexus tumor formationL Dang
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Oncogene 25:487-91. 2006..Our findings indicate that activated Notch3 can function as an oncogene in the developing brain, and link the Notch pathway to human CPT pathogenesis...
- Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathwayTy W Abel
Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, Maryland 21287, USA
J Neuropathol Exp Neurol 64:341-9. 2005..These data support recommendations for genetic testing and screening for CD in patients with LDD and suggest a novel therapy for LDD through pharmacologic inhibition of mTOR...
- Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virusCharles G Eberhart
Department of Pathology, Johns Hopkins University School of Medicine, Ross Bldg 558, 720 Rutland Ave, Baltimore, MD 21205, USA
BMC Cancer 5:19. 2005..We correlated p53 protein expression with pathological subtype and clinical outcome in 75 embryonal brain tumors. The presence of JC virus, which results in p53 protein accumulation, was also examined...
- Genomic amplification of orthodenticle homologue 2 in medulloblastomasKathy Boon
Departments of Neurosurgery and Pathology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Baltimore, MD 21224, USA
Cancer Res 65:703-7. 2005..OTX2 functions to specify the fate of neuroectoderm in various regions of the developing brain. This developmental role is consistent with the evidence suggesting that OTX2 is a medulloblastoma oncogene...