Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma

Basal cell carcinoma (BCC) of the skin is the most common type of cancer, and accounts for up to 40% of all cancers in the United States with a growing incidence rate in the last decades in all developed countries. Surgery is curative for most patients, although it leaves unaesthetic scars, but those that develop locally advanced or metastatic BCC require different therapeutical approaches. Furthermore, patients with BCC present an high risk of developing additional tumors. The increasing economic burden and the morbidity of BCC render of primary interest the development of targeted treatments for this disease. Among the molecular signals involved in the development of BCC, it has become evident the critical role of the morphogenic Hedgehog (Hh) pathway. This pathway is found altered and activated in almost all the BCC, both sporadic or inherited. Given the centrality of the Hh pathway in the pathophysiology of BCC, the primary efforts to identify molecular targets for the topical or systemic treatment of this cancer have focused on the Hedgehog components. Several Hh inhibitors have been so far identified, from the first, the natural cyclopamine to the recently FDA-approved synthetic Vismodegib, most targeting the Hh receptor Smo (either its function or its translocation to the primary cilium). Other molecules await further characterization (Bisamides compounds), while drugs currently approved for other diseases such as Itraconazole (a antimicotic agent) and Vitamin D3 have been tested on BCC with encouraging results. The outcome of the numerous ongoing clinical trials is expected to expand the field in short time. Further research is needed to obtain drugs targeting downstream components of the Hh pathway (eg Gli) or to exploit combinatorial therapies (eg with PI3K inhibitors, or retinoids) in order to overcome potential drug resistance.