Myc Signaling in Medulloblastomas

Summary

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

Top Publications

  1. pmc c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
    Andre O Von Bueren
    Neuro Oncology Program, University Children s Hospital, Zurich, Switzerland
    BMC Cancer 11:74. 2011
  2. ncbi Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastoma
    Yunqing Li
    Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA
    Lab Invest 88:98-111. 2008
  3. pmc Hedgehog signaling promotes medulloblastoma survival via Bc/II
    Eli 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
  4. ncbi Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors
    Xing Fan
    Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Cancer Res 66:7445-52. 2006
  5. ncbi Brief report: S6 ribosomal protein phosphorylation in autistic frontal cortex and cerebellum: a tissue array analysis
    Charles G Eberhart
    Johns Hopkins University, Baltimore, MD, USA
    J Autism Dev Disord 36:1131-5. 2006
  6. pmc Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation
    Xiaohua 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
  7. ncbi c-myc overexpression causes anaplasia in medulloblastoma
    Duncan 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
  8. ncbi Notch3 signaling initiates choroid plexus tumor formation
    L Dang
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Oncogene 25:487-91. 2006
  9. ncbi Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway
    Ty W Abel
    Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, Maryland 21287, USA
    J Neuropathol Exp Neurol 64:341-9. 2005
  10. pmc Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus
    Charles 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

Scientific Experts

  • CHARLES GEORGE EBERHART
  • Duncan Stearns
  • Eli E Bar
  • Andre O Von Bueren
  • Yunqing Li
  • L Dang
  • Xiaohua Su
  • Xing Fan
  • Ty W Abel
  • Kathy Boon
  • Burkhardt Seifert
  • Christoph Oehler
  • Nicolas U Gerber
  • Tarek Shalaby
  • Rolf D Kortmann
  • Katja von Hoff
  • Stefan Rutkowski
  • Martin Pruschy
  • Monika Warmuth-Metz
  • Michael A Grotzer
  • Roger Abounader
  • Xiao Nan Li
  • Qing Shu
  • Fadila Guessous
  • Shongshan Fan
  • David Schiff
  • Bachchu Lal
  • Elizabeth B Johnson
  • John Laterra
  • Leila Khaki
  • Evan Snyder
  • M Wang
  • Yue Ming Li
  • Vidya Gopalakrishnan
  • Gregory Fuller
  • Kenneth Aldape
  • Fredrick F Lang
  • X Fan
  • N Gaiano
  • Sadhan Majumder
  • Jiong Chun
  • William Matsui
  • A Chaudhry
  • Anthony T Yachnis
  • Peter C Burger
  • Hernando Mena
  • James S Nelson
  • Suzanne J Baker
  • Tarik Tihan
  • Melissa M Fraser
  • Gregory J Riggins
  • John Paul Bouffard

Detail Information

Publications11

  1. pmc c-MYC expression sensitizes medulloblastoma cells to radio- and chemotherapy and has no impact on response in medulloblastoma patients
    Andre 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)...
  2. ncbi Functional and molecular interactions between the HGF/c-Met pathway and c-Myc in large-cell medulloblastoma
    Yunqing 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...
  3. pmc Hedgehog signaling promotes medulloblastoma survival via Bc/II
    Eli 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...
  4. ncbi Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors
    Xing 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...
  5. ncbi Brief report: S6 ribosomal protein phosphorylation in autistic frontal cortex and cerebellum: a tissue array analysis
    Charles 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...
  6. pmc Abnormal expression of REST/NRSF and Myc in neural stem/progenitor cells causes cerebellar tumors by blocking neuronal differentiation
    Xiaohua 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...
  7. ncbi c-myc overexpression causes anaplasia in medulloblastoma
    Duncan 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...
  8. ncbi Notch3 signaling initiates choroid plexus tumor formation
    L 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...
  9. ncbi Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway
    Ty 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...
  10. pmc Increased p53 immunopositivity in anaplastic medulloblastoma and supratentorial PNET is not caused by JC virus
    Charles 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...
  11. ncbi Genomic amplification of orthodenticle homologue 2 in medulloblastomas
    Kathy 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...