The dawn of hedgehog inhibitors: Vismodegib

Abstract

Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

Mann med stort hode, lærevansker og multiple basalcellekarsinomer

“…Senere har man vist at signalveien er sentral i utvikling av blant annet basalcellekarsinom. Hemming av signalveien kan benyttes terapeutisk ved basalcellekarsinom (20) kjevecyster. Slike cyster kan bli store, og tennene kan bli forskjøvet (6,8).…”

“…Disse preparatene kalles «hedgehoghemmere» (ramme 2) (20). De virker ved å blokkere signalveien som, på grunn av genfeil i PTCH1, er aktivert ved utvikling av basalcellekarsinomer hos alle pasienter -ikke bare ved Gorlins syndrom (21,22).…”

Targeted Therapy in Advanced Gastric Cancer: An Updated Review

“…In 2012, the Hh inhibitor vismodegib was approved for the treatment of basal-cell carcinoma in the United States [126]. However, a randomized phase II study using vismodegib with FOLFOX compared to FOLFOX alone in patients with advanced or metastatic gastric and GEJ carcinoma in the first-line setting did not improve survival.…”

Cancer and cancer stem cell targeting agents : A focus on salinomycin and apoptin

“…FDA recently approved vismodegib for the treatment of basal cell carcinoma; this drug targets the protein smo because these tumor cells possess an active hedgehog signaling pathway [38][39][40][41] . This has initiated interest in blocking similar signaling pathways to treat other cancers.…”

“…Vismodegib's success in treating basal cell carcinoma is only partial, however, some resistant tumors develop. This drug was further tested for use in treating medullablastoma and pancreatic tumors 40 . Similarly, inhibitors of the Wnt/β-catenin and notch signaling pathways were also explored, however, the abysmal results obtained from treating ovarian and colorectal cancers with vismodegib made researchers cautions when using inhibitors of crucial signaling pathways that are important for normal tissue and stem cell function 40 .…”