Next generation hedgehog inhibitor for invasive basal cell carcinoma
Project Abstract:
Vismodegib is the firstinclass hedgehog Hh pathway inhibitor for the treatment of locally advanced and metastatic basal cell carcinomas BCCs Systemic use of Vismodegib provided an unprecedented solution for invasive or inoperable BCCs However only 3040 eligible patients responded to Vismodegib and treatment resistance developed within months of treatment The next generation Hh inhibitors which act downstream of Smo are expected to be able to overcome drug resistance Recently it was discovered that the processing of Gli transcription factors direct targets of the Hh signaling pathway is reliant on the intraflagellar transport IFT machinery We found that some components of IFT function exclusively in the Hh pathway and disrupting genes encoding these IFT proteins can block the formation of BCC in vivo suggesting that these IFT proteins are attractive therapeutic targets In this proposal we aim to screen small molecule inhibitors of specific IFT proteins and determine whether IFT inhibitors can suppress the Hh signaling pathway and block BCC progression We anticipate that IFT inhibitors can achieve comparable therapeutic efficacy to Vismodegib More importantly IFT inhibitors may be used to treat BCCs that do not exhibit initial respond to Vismodegib or BCCs that develop resistance to Vismodegib
