Hedgehog pathway

Targeting the hedgehog pathway

The most common way to target this pathway is modulate SMO. Antagonist and agonist of SMO have already shown to affect the pathway regulation downstream. Several hedgehog signaling pathway inhibitors are available for cancer treatment, such as vismodegib and sonidegib. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers. SMO inhibitors represent a potential treatment for some types of cancers. However, because of harmful and potentially toxic side-effects of SMO inhibitors, undetermined safety in children, and the evidence that some patients develop resistance to SMO inhibitors, new classes of drugs are needed. The most clinically advanced SMO targeting agents are cyclopamine-competitive. Itraconazole (Sporanox) has also been shown to target SMO through a mechanism distinct from cyclopamine and vismodegib. Itraconazole (ITZ) inhibits SMO in the presence of mutations conferring resistance to vismodegib and other cyclopamine-competitive antagonists, like IPI-926 and Novartis' LDE-225. PTCH and Gli3 (5E1) antibodies are also a way to regulate the pathway. A downstream effector and strong transcriptional activator siRNA Gli1 has been used to inhibit cell growth and promote apoptosis. Arsenic trioxide (Trisenox) has also been shown to inhibit hedgehog signaling by interfering with Gli function and transcription.