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E-GEOD-77042 - Inhibition of Medulloblastoma growth by a sonic hedgehog (SHH) inhibitor

Status
Released on 14 March 2016, last updated on 19 March 2016
Organism
Mus musculus
Samples (75)
Array (1)
Protocols (7)
Description
Aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of many cancers, including medulloblastoma and basal cell carcinoma (BCC). In this study, using neonatally irradiated Ptch1+/- mice as a model of Hh-dependent tumors, we investigated the in vivo effects of MK-4101, a novel SMO antagonist, for treatment of medulloblastoma and BCC. Results clearly demonstrate a robust antitumor activity of MK-4101, achieved through the inhibition of proliferation and induction of extensive apoptosis in tumor cells. Of note, beside antitumor activity on transplanted tumors, MK-4101 was highly efficacious against primary medulloblastoma and BCC developing in the cerebellum and skin of Ptch1+/- mice. By identifying the changes induced by MK-4101 in gene expression profiles in tumors, we also elucidate the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in the tumor cells, showing the maximum inhibitory effect on Gli1 activity. MK-4101 also induced deregulation of cell cycle and block of DNA replication in tumors. Members of the IGF and Wnt signaling pathways , were among the most highly deregulated genes by MK-4101, suggesting that the interplay among Hh, IGF and Wnt is crucial in Hh-dependent tumorigenesis. Altogether, the results of this preclinical study support a therapeutic opportunity for MK-4101 in the treatment of Hh-driven cancers, also providing useful information for combination therapy with drugs targeting pathways cooperating with Hh oncogenic activity. Gene expression data was generated (in replicates) from Medulloblastoma allografts collected at various time points and following low (40mpk) or high (80 mpk) or vehicle single dose (QD) or mutiple dose (BID) treatment with a SHH pathway inhibitor.
Experiment type
transcription profiling by array 
Contacts
Anna Saran, Armin Lahm, Christian Steinkühler, Emanuela Pasquali, Fabrizio Colaceci, Gessica Filocamo, Mariateresa Mancuso, Mirella Tanori, Mirko Brunetti, Romina Sasso, Simonetta Pazzaglia
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-77042.idf.txt
Sample and data relationshipE-GEOD-77042.sdrf.txt
Processed data (1)E-GEOD-77042.processed.1.zip
Array designA-GEOD-6794.adf.txt
Links