Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Abstract

The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with development of several types of cancer, including basal cell carcinoma and acute promyelocytic leukemia (APL) among many others. Inactivating mutations in Patched 1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types but most prominent in basal cell carcinoma. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, there are only three FDA-approved drugs for cancers that affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide (ATO), which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the efficacy and safety of these clinically-approved drugs targeting the Shh pathway along with a discussion on other Shh pathway inhibitors being developed.

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

“…Surgery and radiotherapy are often not viable options for advanced BCCs, supporting the need for alternatives. Inhibition of the hedgehog (Hh) signaling pathway is among the few treatment options available for patients with advanced BCCs [9,10]. The Hh signaling pathway is a key regulator of cell growth and differentiation during embryonic development, but it is mostly silenced in adults, with only limited activity in some processes, including hair growth and maintenance of taste.…”

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer

“…VEGF/VEGFR2, Ang/Tie2 and PDGF/PDGFR2 signaling pathway have been certified to be involved in Shh-mediated angiogenesis [22][23][24] . In addition, several Shh/Gli 1 signaling pathway inhibitors have been demonstrated to suppress tumor growth and angiogenesis 25,26 .…”

Crocetin suppresses angiogenesis through inhibiting Sonic hedgehog signaling pathway in gastric cancer

“…As a new recognized pro-angiogenic factor, Sonic hedgehog (Shh) binds to its receptor Patched (PTCH) and then induces release of smoothened (SMO), which mediates downstream activation of Gli1, regulating various target genes involved in cell growth and angiogenesis [27,28]. Activation of Shh/Gli1 signaling pathway has been observed during cancer angiogenesis process [29] and several inhibitors targeting Shh/Gli1 pathway show suppressing effects on tumor growth and angiogenesis [30,31]. Therefore, we designed this research to clarify the effects of crocetin on angiogenesis and VM formation in GC, and to explore its potential targeting signaling, such as Shh/Gli1 pathway.…”