Hedgehog (Hh) signaling is implicated in regulation of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. Since the first link of Hh signaling to cancer through studies of Gorlin syndrome in 1996, it has been shown to be involved in many types of cancer, including skin, leukemia, lung, brain, and gastrointestinal cancers. In recent years, there has been significant progress regarding Hh signaling and its significance in cancer development and therapeutics.Meanwhile, rapid advancement in the discovery of novel Hh signaling inhibitors has provided many opportunities for developing novel cancer therapeutic strategies.
There are three major targeting sites for Hh signaling inhibitors identified so far: Hh molecules (ligands), SMO protein (signal transducer smoothened), and Gli inhibitors ( transcription factors). More than 200 compounds have been disclosed to have inhibitory effects on Hh signaling, eight of which have been used for clinical trials. The most successful clinical trials are of GDC-0449 targeting SMO in BCCs. In early 2012, the US Food and Drug Administration approved the clinical use of Hh inhibitor GDC-0449 (Erivedge/vismodegib) for treatment of locally advanced and metastatic basal cell carcinomas (BCCs). However, an early clinical trial on a medulloblastoma patient using GDC-0449 yielded only a transient therapeutic effect, due to an SMO mutation occurring soon after treatment. In other words, Hh signaling inhibitors has different effects in different cancers, even in different subtypes in the same cancer. As a result, there’s still a long way to develop valid cancer therapeutic strategies targeting Hh signaling.