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  1. Article: Targeting medulloblastoma: small-molecule inhibitors of the Sonic Hedgehog pathway as potential cancer therapeutics.

    Romer, Justyna / Curran, Tom

    Cancer research

    2005  Volume 65, Issue 12, Page(s) 4975–4978

    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor for which no satisfactory treatments exist. The Sonic Hedgehog signaling pathway seems to play an important role in the pathology of this disease. Here we review our recent demonstration ... ...

    Abstract Medulloblastoma is the most common malignant pediatric brain tumor for which no satisfactory treatments exist. The Sonic Hedgehog signaling pathway seems to play an important role in the pathology of this disease. Here we review our recent demonstration that a small-molecule inhibitor of this pathway can regress tumors that arise in a transgenic mouse model of medulloblastoma. These and other findings suggest that inhibitors of Sonic Hedgehog signaling may offer an effective way to target some malignancies.
    MeSH term(s) Animals ; Benzimidazoles/pharmacology ; Brain Neoplasms/drug therapy ; Disease Models, Animal ; Hedgehog Proteins ; Humans ; Medulloblastoma/drug therapy ; Mice ; Mice, Transgenic ; Signal Transduction/drug effects ; Trans-Activators/antagonists & inhibitors ; Trans-Activators/physiology
    Chemical Substances Benzimidazoles ; Hedgehog Proteins ; SHH protein, human ; Trans-Activators
    Language English
    Publishing date 2005-06-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-05-0481
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Medulloblastoma and retinoblastoma: oncology recapitulates ontogeny.

    Romer, Justyna T / Curran, Thomas

    Cell cycle (Georgetown, Tex.)

    2004  Volume 3, Issue 7, Page(s) 917–919

    Abstract: One major factor hindering progress of pediatric cancers of the nervous system has been the lack of satisfactory model systems for testing novel therapies. A mouse strain, mutant for the Rb1 gene was generated 12 years ago in the hope of producing a ... ...

    Abstract One major factor hindering progress of pediatric cancers of the nervous system has been the lack of satisfactory model systems for testing novel therapies. A mouse strain, mutant for the Rb1 gene was generated 12 years ago in the hope of producing a model in which to study retinoblastoma. Surprisingly, the Rb(+/-) mice never developed retinoblastoma. Now, Zhang, Schweers and Dyer produce triply deficient Rb, p107 and p53 mutant retinal progenitor cells. All such mice develop intraocular retinoblastoma with invasion of the tumor into the anterior chamber of the eye. This dramatic finding represents the first description of a heritable mouse model of retinoblastoma, which has eluded investigators for the last 12 years. Such models provide an unprecedented opportunity to advance knowledge of tumorigenesis and to develop non-toxic intervention strategies which eradicate disease.
    MeSH term(s) Animals ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Disease Models, Animal ; Genetic Predisposition to Disease/genetics ; Humans ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Medulloblastoma/therapy ; Mice ; Mice, Knockout ; Retinoblastoma/genetics ; Retinoblastoma/metabolism ; Retinoblastoma/therapy ; Retinoblastoma Protein/genetics ; Retinoblastoma-Like Protein p107/genetics ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Retinoblastoma Protein ; Retinoblastoma-Like Protein p107 ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2004-07-08
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: The hedgehog pathway and neurological disorders.

    Dellovade, Tammy / Romer, Justyna T / Curran, Tom / Rubin, Lee L

    Annual review of neuroscience

    2006  Volume 29, Page(s) 539–563

    Abstract: The hedgehog pathway is a major regulator of embryonic development, and mutations that decrease its activity are known to be associated with severe defects in nervous system development. Recent evidence suggests hedgehog continues to function in adult ... ...

    Abstract The hedgehog pathway is a major regulator of embryonic development, and mutations that decrease its activity are known to be associated with severe defects in nervous system development. Recent evidence suggests hedgehog continues to function in adult tissue, normal as well as diseased, by regulating both cell proliferation and the production of growth and angiogenic factors. In the adult nervous system, this dual ability is especially important in regulating the behavior of neural stem and progenitor cells. This review summarizes information connecting hedgehog signaling and neural diseases, including neurodegenerative disorders and brain tumors, particularly medulloblastoma. We also describe the discovery and utility of small molecule agonists and antagonists of this pathway and their potential as novel types of therapeutics.
    MeSH term(s) Animals ; Cell Cycle/drug effects ; Cell Cycle/physiology ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/metabolism ; Enzyme Inhibitors/therapeutic use ; Hedgehog Proteins ; Humans ; Medulloblastoma/drug therapy ; Medulloblastoma/metabolism ; Nervous System Diseases/classification ; Nervous System Diseases/drug therapy ; Nervous System Diseases/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Stem Cells/drug effects ; Stem Cells/physiology ; Trans-Activators/agonists ; Trans-Activators/antagonists & inhibitors ; Trans-Activators/metabolism
    Chemical Substances Enzyme Inhibitors ; Hedgehog Proteins ; Trans-Activators
    Language English
    Publishing date 2006
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 282459-0
    ISSN 1545-4126 ; 0147-006X
    ISSN (online) 1545-4126
    ISSN 0147-006X
    DOI 10.1146/annurev.neuro.29.051605.112858
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1433: Show issues Location:
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  4. Article: Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor.

    Sasai, Ken / Romer, Justyna T / Kimura, Hiromichi / Eberhart, Derek E / Rice, Dennis S / Curran, Tom

    Cancer research

    2007  Volume 67, Issue 8, Page(s) 3871–3877

    Abstract: The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory ... ...

    Abstract The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.
    MeSH term(s) Animals ; Female ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Hedgehog Proteins/metabolism ; Medulloblastoma/drug therapy ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Nude ; Patched Receptors ; Patched-1 Receptor ; Receptors, CXCR ; Receptors, CXCR6 ; Receptors, Cell Surface/biosynthesis ; Receptors, Cell Surface/genetics ; Receptors, Chemokine/genetics ; Receptors, Chemokine/metabolism ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/metabolism ; Smoothened Receptor
    Chemical Substances Cxcr6 protein, mouse ; Hedgehog Proteins ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; Receptors, CXCR ; Receptors, CXCR6 ; Receptors, Cell Surface ; Receptors, Chemokine ; Receptors, G-Protein-Coupled ; Shh protein, mouse ; Smo protein, mouse ; Smoothened Receptor
    Language English
    Publishing date 2007-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-07-0493
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies.

    Sasai, Ken / Romer, Justyna T / Lee, Youngsoo / Finkelstein, David / Fuller, Christine / McKinnon, Peter J / Curran, Tom

    Cancer research

    2006  Volume 66, Issue 8, Page(s) 4215–4222

    Abstract: Gene expression profiling indicates that the Sonic Hedgehog (Shh) pathway is active in approximately 30% of human medulloblastomas, suggesting that it could provide a useful therapeutic target. Previously, we showed that spontaneous medulloblastomas in ... ...

    Abstract Gene expression profiling indicates that the Sonic Hedgehog (Shh) pathway is active in approximately 30% of human medulloblastomas, suggesting that it could provide a useful therapeutic target. Previously, we showed that spontaneous medulloblastomas in Ptc1(+/-)p53-/- mice could be eradicated by treatment with a small-molecule inhibitor (HhAntag) of Smoothened (Smo). Here, we compared the responses of mouse medulloblastoma cells propagated in flank allografts, either directly or after culture in vitro, to HhAntag. We found that Shh pathway activity was suppressed in medulloblastoma cells cultured in vitro and it was not restored when these cells were transplanted into the flank of nude mice. The growth of these transplanted tumor cells was not inhibited by treatment of mice with doses of HhAntag that completely suppressed Smo activity. Interestingly, tumor cells transplanted directly into the flank maintained Smo activity and were sensitive to treatment with HhAntag. These findings indicate that propagation of tumor cells in culture inhibits Smo activity in a way that cannot be reversed by transplantation in vivo, and they raise concerns about the use of cultured tumor cells to test the efficacy of Shh pathway inhibitors as anticancer therapies.
    MeSH term(s) Animals ; Cell Line, Tumor ; Down-Regulation ; Female ; Gene Expression Profiling ; Hedgehog Proteins ; Medulloblastoma/drug therapy ; Medulloblastoma/genetics ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface/genetics ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Smoothened Receptor ; Trans-Activators/antagonists & inhibitors ; Trans-Activators/metabolism ; Tumor Suppressor Protein p53/genetics
    Chemical Substances Hedgehog Proteins ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; Receptors, Cell Surface ; Receptors, G-Protein-Coupled ; Shh protein, mouse ; Smo protein, mouse ; Smoothened Receptor ; Trans-Activators ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2006-04-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-05-4505
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice.

    Romer, Justyna T / Kimura, Hiromichi / Magdaleno, Susan / Sasai, Ken / Fuller, Christine / Baines, Helen / Connelly, Michele / Stewart, Clinton F / Gould, Stephen / Rubin, Lee L / Curran, Tom

    Cancer cell

    2004  Volume 6, Issue 3, Page(s) 229–240

    Abstract: Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major long-term side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a ... ...

    Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major long-term side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.
    MeSH term(s) Animals ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Division ; Disease-Free Survival ; Dose-Response Relationship, Drug ; Hedgehog Proteins ; Kruppel-Like Transcription Factors ; Medulloblastoma/drug therapy ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; Mice ; Mice, Transgenic ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction ; Smoothened Receptor ; Trans-Activators/antagonists & inhibitors ; Transcription Factors/metabolism ; Tumor Cells, Cultured ; Zinc Finger Protein GLI1
    Chemical Substances Gli protein, mouse ; Hedgehog Proteins ; Kruppel-Like Transcription Factors ; Receptors, G-Protein-Coupled ; Shh protein, mouse ; Smo protein, mouse ; Smoothened Receptor ; Trans-Activators ; Transcription Factors ; Zinc Finger Protein GLI1
    Language English
    Publishing date 2004-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccr.2004.08.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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