SOMATIC CELL TRANSFER TO MODEL MEDULLOBLASTOMA IN MICE

Summary

Principal Investigator: DANIEL WEBSTER FULTS
Abstract: DESCRIPTION (provided by applicant): Medulloblastomas (MBs) are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Aggressive treatment approaches combining surgery, craniospinal radiation, and chemotherapy result in 5-year survival rates exceeding 70%. Treatment- related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral brain damage. The overall objective of this research is to use a mouse model of MB, which we developed using the RCAS/tv-a gene transfer system, as a preclinical testing platform for molecular targeted MB therapy. This experimental system uses a retroviral vector (RCAS) derived from avian leukosis virus and a transgenic mouse line that expresses the retrovirus receptor under control of the Nestin gene promoter, which is active in neural progenitor cells during normal cerebellar development. Using this system, we showed that ectopic expression of Sonic Hedgehog (Shh) in the postnatal cerebellum induces MBs in mice. Furthermore, we identified proteins belonging to different functional classes that cooperate with Shh to enhance MB formation. These enhancing factors are (a) Myc oncoproteins, which stimulate proliferation of neural progenitors during normal development, (b) Bcl-2, which potently inhibits apoptosis, (c) insulin-like growth factor-II, which concomitantly stimulates proliferation and blocks apoptosis by activating the phosphatidylinositol 3-kinase (PI3K) signal transduction pathway, and (d) hepatocyte growth factor (HGF), a growth factor with pleiotropic effects on tumor growth. The fact that all of these proteins are highly expressed in human MBs indicates that their tumor-promoting activity in mice accurately reflects the pathogenesis of the human disease. Moreover, these proteins and their downstream signaling molecules can be considered therapeutic targets. Specific aim 1 is to determine whether inhibiting Shh signaling cooperates with blockade of HGF signaling to enhance treatment response in mice bearing Shh?induced MBs. Specific aim 2 is to determine whether MB growth suppression by HGF monoclonal antibody therapy can be enhanced by pharmacologic inhibition of the HGF receptor c- Met or downstream PI3K signaling. Specific aim 3 is to use the RCAS/tv-a system to identify genes that cause Shh-induced MBs to metastasize to the spine. Spinal metastasis is a highly unfavorable prognostic factor for patients with MBs. Achievement of these aims will make it possible to translate the mechanistic discoveries to molecular targeted therapies for children with MB.
Funding Period: 2004-07-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. ncbi N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma
    Samuel R Browd
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132 2303, USA
    Cancer Res 66:2666-72. 2006
  2. ncbi Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic hedgehog-dependent medulloblastoma formation in mice
    Todd D McCall
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 67:5179-85. 2007
  3. pmc Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth
    Mandy J Binning
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 68:7838-45. 2008
  4. pmc Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma
    Valerie Coon
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Mol Cancer Ther 9:2627-36. 2010
  5. pmc The genetic landscape of the childhood cancer medulloblastoma
    D Williams Parsons
    Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Science 331:435-9. 2011
  6. pmc Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma
    Tiffany Doucette
    Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Int J Cancer 129:2093-103. 2011
  7. pmc WIP1 enhances tumor formation in a sonic hedgehog-dependent model of medulloblastoma
    Tiffany A Doucette
    Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Neurosurgery 70:1003-10; discussion 1010. 2012
  8. pmc Clonal selection drives genetic divergence of metastatic medulloblastoma
    Xiaochong Wu
    Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
    Nature 482:529-33. 2012
  9. pmc Functional genomics identifies drivers of medulloblastoma dissemination
    Michael Mumert
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 72:4944-53. 2012

Research Grants

  1. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013

Detail Information

Publications9

  1. ncbi N-myc can substitute for insulin-like growth factor signaling in a mouse model of sonic hedgehog-induced medulloblastoma
    Samuel R Browd
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132 2303, USA
    Cancer Res 66:2666-72. 2006
    ..Thus, Shh has transforming functions in addition to induction of N-myc and Gli1. This tumor model will be useful for testing novel medulloblastoma therapies and providing insight into mechanisms of hedgehog-mediated transformation...
  2. ncbi Apoptosis suppression by somatic cell transfer of Bcl-2 promotes Sonic hedgehog-dependent medulloblastoma formation in mice
    Todd D McCall
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 67:5179-85. 2007
    ..These findings provide insights into the molecular signals that initiate medulloblastoma formation and they support the importance of blocking apoptosis in carcinogenesis...
  3. pmc Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth
    Mandy J Binning
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 68:7838-45. 2008
    ..These findings indicate a role for HGF in medulloblastoma initiation and growth and show efficacy of HGF-targeted therapy in a mouse model of endogenously arising tumors...
  4. pmc Molecular therapy targeting Sonic hedgehog and hepatocyte growth factor signaling in a mouse model of medulloblastoma
    Valerie Coon
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Mol Cancer Ther 9:2627-36. 2010
    ....
  5. pmc The genetic landscape of the childhood cancer medulloblastoma
    D Williams Parsons
    Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA
    Science 331:435-9. 2011
    ....
  6. pmc Bcl-2 promotes malignant progression in a PDGF-B-dependent murine model of oligodendroglioma
    Tiffany Doucette
    Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
    Int J Cancer 129:2093-103. 2011
    ..Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype...
  7. pmc WIP1 enhances tumor formation in a sonic hedgehog-dependent model of medulloblastoma
    Tiffany A Doucette
    Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Neurosurgery 70:1003-10; discussion 1010. 2012
    ..Although p53 deficiency enhances tumor formation in mice, inactivation of the p53 gene is seen in a minority of MBs. Wild-type p53-induced phosphatase 1 (WIP1) downregulates p53 expression and has been shown to be overexpressed in MBs...
  8. pmc Clonal selection drives genetic divergence of metastatic medulloblastoma
    Xiaochong Wu
    Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
    Nature 482:529-33. 2012
    ..Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies...
  9. pmc Functional genomics identifies drivers of medulloblastoma dissemination
    Michael Mumert
    Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Cancer Res 72:4944-53. 2012
    ....

Research Grants30

  1. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
    ..These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation. ..
  2. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..