Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives

Abstract

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed.

Keywords: basal cell carcinoma; hedgehog inhibitors; keratinocyte carcinoma; smoothened inhibitors; sonidegib; topical delivery; vismodegib.

Figure 1

The main components of the hedgehog pathway. Membrane proteins are either blue or red, inactive proteins are green and active proteins are colored pink. The red crosses indicate target proteins for hedgehog inhibitors (HHis). In canonical hedgehog (HH) signaling, HH ligands are modified by hedgehog acyltransferase (HHAT) and released from HH-secreting cells. HH ligands then bind to the cell membrane protein patched (PTCH), which leads to release of smoothened (SMO). SMO moves to the primary cilium where it prevents breakdown of GLI family zinc finger proteins (GLI) allowing them to translocate to the nucleus and promote expression of HH-signaling target genes. In basal cell carcinomas (BCCs), inactivating PTCH1 mutations are most common (70–90%) followed by activating SMO mutations (10–20%). Created with BioRender.com.