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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Molecular Medicine in Practice

Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma

Valerie Coon, Tamara Laukert, Carolyn A. Pedone, John Laterra, K. Jin Kim and Daniel W. Fults
Valerie Coon
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Tamara Laukert
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Carolyn A. Pedone
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John Laterra
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K. Jin Kim
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Daniel W. Fults
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DOI: 10.1158/1535-7163.MCT-10-0486 Published September 2010
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    Figure 1.

    Histopathology of medulloblastomas induced by Shh + HGF. A and B, coronal brain sections showing tumor in the cerebellum and fourth ventricle (A) and obstructive hydrocephalus in the forebrain (B; H&E). C, classic medulloblastoma pattern showing homogeneous sheets of undifferentiated tumor cells (H&E). D, MBEN pattern in which round, neurocytic-appearing tumor cells are arrayed in a linear pattern (top left and inset) adjacent to an area of disorganized cytoarchitecture characteristic of the classic pattern (right; H&E). E, immunoperoxidase staining showing that MBEN areas (left) have abundant immunoreactivity for neuronal differentiation marker NeuN compared with classic-appearing areas (right). F, immunoperoxidase staining showing that Ki67 staining is absent in the MBEN area (left) compared with the actively proliferating cells in the classic-appearing area (right). Scale bars, 500 μm (A and B), 25 μm (C and D, inset), and 50 μm (D–F).

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    Figure 2.

    Response to Shh- and HGF-targeted therapy in mice with medulloblastomas. Kaplan-Meier survival analysis of mice injected with RCAS-Shh and RCAS-HGF on day 0 and then treated with the indicated therapeutic agents starting on day 14 (arrow). A and B, results from two independent experiments.

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    Figure 3.

    Analysis of proliferation and apoptosis in Shh + HGF–induced medulloblastomas. Bar graphs and representative photomicrographs showing the percentage (mean ± SEM) of tumor cells with positive immunoreactive staining for Ki67 (proliferation index; A) and cleaved caspase-3 (apoptotic index; B) in Shh + HGF–induced medulloblastomas from mice treated with the indicated therapeutic agents. Scale bars, 25 μm.

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    Figure 4.

    Analysis of Shh and HGF signaling in response to molecular-targeted therapy. Bar graphs and representative photomicrographs showing the percentage (mean ± SEM) of tumor cells with positive immunoreactive staining for Gli2 in the nucleus (Gli2 index; A) and phosphorylated c-Met in the cytoplasm (pc-Met index; B) in medulloblastomas from mice treated with the indicated therapeutic agents. Phototmicrographs in B show pc-Met+ tumor cells (right) adjacent to cerebellar cortex (left). Scale bars, 25 μm (A) and 50 μm (B).

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    Four-month survival analysis of Ntv-a mice with Shh + HGF–induced medulloblastomas

    Therapeutic agentDosing regimenNo. of mice analyzedMedian survival (d)P
    5G82.5 mg/kg i.p. twice weekly6023—
    L2G72.5 mg/kg i.p. twice weekly581110.03
    Cyclopamine + 5G810 mg/kg i.p. every other day + 5G860620.04
    L2G7 + cyclopamineSee above regimens59470.8
    5E15.0 mg/kg i.p. twice weekly34>1020.04

    NOTE: P values were derived from log-rank tests comparing cumulative survival of each test group with 5G8 control. The P value for the cyclopamine group was calculated over a 90-d observation period.

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    Molecular Cancer Therapeutics: 9 (9)
    September 2010
    Volume 9, Issue 9
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    Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma
    Valerie Coon, Tamara Laukert, Carolyn A. Pedone, John Laterra, K. Jin Kim and Daniel W. Fults
    Mol Cancer Ther September 1 2010 (9) (9) 2627-2636; DOI: 10.1158/1535-7163.MCT-10-0486

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    Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma
    Valerie Coon, Tamara Laukert, Carolyn A. Pedone, John Laterra, K. Jin Kim and Daniel W. Fults
    Mol Cancer Ther September 1 2010 (9) (9) 2627-2636; DOI: 10.1158/1535-7163.MCT-10-0486
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