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

Cancers
Tadas K RimkusHui-Wen Lo

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 t...Continue Reading

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Methods Mentioned

BETA
transgenic
xenograft
xenografts

Clinical Trials Mentioned

NCT01835626
NCT02639117
NCT02067104
NCT01631331
NCT01815840
NCT01700049
NCT01898598
NCT02436408
NCT01367665
NCT01556009

Software Mentioned

Circadian

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