title: MK-4101, a Potent Inhibitor of the Hedgehog Pathway, Is Highly Active against Medulloblastoma and Basal Cell Carcinoma.
abstract: 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 the treatment of medulloblastoma and BCC. Results clearly demonstrated 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 elucidated the mechanism of action of this novel, orally administrable compound. MK-4101 targets the Hh pathway in tumor cells, showing the maximum inhibitory effect on Gli1 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. Mol Cancer Ther; 15(6); 1177-89. ©2016 AACR.
authors.affiliation: Exiris, Rome, Italy. gessica_filocamo@exiris.it simonetta.pazzaglia@enea.it.
authors.forename: Gessica
authors.initials: G
authors.lastname: Filocamo
authors.affiliation: Exiris, Rome, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Brunetti
authors.affiliation: IRBM Science Park, Pomezia, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Colaceci
authors.affiliation: IRBM Science Park, Pomezia, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Sasso
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Tanori
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasquali
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.affiliation: Independent expert, Rome, Italy.
authors.forename: Armin
authors.initials: A
authors.lastname: Lahm
authors.affiliation: Department of Molecular Medicine, University La Sapienza, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: Exiris, Rome, Italy. Italfarmaco, Cinisello Balsamo, Milan, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Steinkühler
authors.affiliation: Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA) CR-Casaccia, Rome, Italy. gessica_filocamo@exiris.it simonetta.pazzaglia@enea.it.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D002280:Basal Cell Carcinoma / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D007555:Isoxazoles; C000620841:MK-4101; D014230:Triazoles