Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

Abstract

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

Pituitary stem cell regulation: who is pulling the strings?

“…Unraveling the nature of these connections may reveal interesting and valuable therapeutic targets and lead to new approaches for treating pituitary tumors. For example, the SHH pathway may be inhibited by SMO antagonists, which has been shown as a promising perspective for treating ACP (Rimkus et al 2016), and 234:3 blocking CXCR4 signaling may impede pituitary tumor growth (Barbieri et al 2014, Mertens et al 2015.…”

Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

“…A variety of inhibitors have been developed to target different levels of hedgehog/Gli signaling, including suppression of SMO, interference with the hedgehog/patched interaction, and direct inhibition of Gli signaling. These compounds include SMO inhibitors such as vismodegib and sonidegib, two Food and Drug Administration-approved inhibitors, and others, such as BMS-833923, IPI-926, PF-04449913, and LY2940680, which are currently in clinical trials (46,47). However, a variety of oncogenic pathways, including Kras, TGF-␤, PI3K-AKT, FIGURE 6.…”

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…Among these three ligands, SHh is the most widely expressed in mammalian tissues, while IHh is specific for bone development and DHh expression is restricted to gonads (29,30). The receptor for Hh ligands is a protein with 12 transmembrane domains termed patched 1 (PTCH1), which is located in the cell membrane (31). Another transmembrane protein called smoothened (SMO) is also involved in the Hh signaling pathway, while GLIs are zinc-finger proteins that function as translational modulators of this pathway (32).…”