Basal Cell Carcinoma and the Carcinogenic Role of Aberrant Hedgehog Signaling

Anna Saran


Future Oncol. 2010;6(6):1003-1014. 

In This Article

Targeted Therapy of BCC

Although surgery remains the elective treatment for localized BCC, our ever-increasing understanding of the signaling pathways that contribute to BCC and other Shh-related tumors provides opportunities for therapeutic applications, and new pharmacological options are being tested. In 1970 cyclopamine, a steroidal alkaloid from Veratrum, was described as a potent teratogen capable of inducing cyclopia and other birth defects in rabbits.[142] Later it became clear that cyclopamine and other related Veratrum alkaloids specifically block Hh signaling,[143] and that inhibition occurs by direct binding to Smo.[144] Oral administration of cyclopamine inhibited the growth of UV-induced BCCs in Ptch1+/- mice,[145] and was demonstrated to considerably reduce medulloblastoma growth in Ptch1+/−/p53−/− compound mutant mice.[146] However, therapeutic usage of this naturally occurring small-molecule Hh antagonist is problematic owing to its several serious side effects (e.g., teratogenic activity causing cyclopia and holoprosencephaly[147]). Cyclopamine discovery and molecular characterization, however, has strongly encouraged the development of several synthetic small-molecule Hh antagonists (reviewed in Keeler and Binns[147]). Among these, CUR61414 from Curis (MA, USA)/Genentech (CA, USA) was tested ex vivo with positive results on mouse embryonic skin punches or adult mouse skin explants containing BCC-like lesions,[148] but failed to cause regression of sporadic human BCCs when topically applied in a Phase 1 clinical trial.[149] A second Curis/Genentech Hh inhibitor (GDC-0449) has been successfully tested in a Phase 1 trial, with disease responses occurring in eight of nine patients with complicated or metastatic BCC.[150] Mutations of Ptch1, Smo and Sufu are detected in a large proportion (>60%) of sporadic human tumors, nevertheless this leaves a considerable fraction (>30%) representing unknown underlying molecular sources of Hh deregulation. This strongly suggests that additional genetic defects must be involved. Eventually, mutations of further genes in the Hh or other pathways will be discovered in sporadic BCCs, providing additional molecular targets for therapeutic intervention.


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