83 Cyclopamine displayed anti-tumor activity in vitro and in vivo, but poor oral bioavailability and acid sensitivity has prevented further clinical development. clearly One clinical report of four patients with BCC, one of whom had Gorlin syndrome, described dramatic, rapid clinical regression of the lesions in response to topical cyclopamine application versus placebo. In addition, histological and immunohistochemical analysis showed apoptosis and increased markers of differentiation in response to Hh inhibition.84 Although no longer in clinical development due to increased potency and bioavailability of cyclopamine derivatives, cyclopamine remains an important agent in preclinical models of Hh inhibition. Itraconazole Interestingly, the anti-fungal agent itraconazole was found to have Hh inhibitory properties on a drug screen of known compounds.

Kim et al showed that commonly used doses of itraconazole suppressed Hh pathway activity and inhibited growth of medulloblastoma in vivo. It appears to act on Smo, as does cyclopamine and its synthetic derivatives, but its mechanism of Smo antagonism is distinct from that of cyclopamine and appears to limit the ciliary accumulation of Smo.85 Itraconazole is currently in studies of patients with BCC, metastatic prostate cancer, and recurrent non-small cell lung cancer (see Table 1). Table 1 Smoothened inhibitors currently in clinical trials for cancer Synthetic and semi-synthetic cyclopamine derivatives All of the Hh inhibitors in clinical trials currently act at the level of Smo (see Table 1 for a list of currently open clinical trials and Table 2 for a summary of findings of Smo inhibitors in clinical trials).

Due to the decreased oral bioavailability and acid sensitivity of cyclopamine, semi-synthetic and synthetic derivatives have been developed. These derivatives appear to have increased potency and all are oral agents. Smo inhibitors currently under investigation appear to inhibit Smo through binding at the same portion of the transmembrane segment 6.86,87 Here, we will review the published or presented data regarding Smo inhibitors in clinical trials for cancer. Table 2 Summary of clinical findings from Phase I trials of Smoothened inhibitors in cancer Vismodegib Early results from patients with medulloblastoma and BCC on the initial Phase I study of GDC-0449 were published in the New England Journal of Medicine in 2009 demonstrating a role for Smo inhibitors in cancers known to be driven by Hh pathway mutations.

88,89 In the first report, one patient with heavily pre-treated Brefeldin_A medulloblastoma had clinical and radiographic regression of widespread systemic metastases on vismodegib. These results were short-lived, however, with measurable increases in tumor size at 3 months of therapy and subsequent identification of a single amino acid substitution conferring resistance.