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Tuesday, 20 Mar, 2018
Winning the War on Cancer
The Wnt (pronounced “Wint”) family is an important group of signalling proteins that reside on the plasma membrane. Wnt signalling pathways play a critical role in various complex biological systems, including embryonic development and tissue regeneration. It has been shown that the malfunction of Wnt signalling, specifically increased Wnt signalling, can lead to the growth and spread of cancer.
Scientists from Duke-NUS Medical School have discovered a way to selectively target and destroy cancer tumours with certain mutations that increase Wnt signalling. These are known as “Wnt-addicted” tumours, and are commonly found in colorectal, ovarian and pancreatic cancers.
Hitting the Right Target with the Right Drug
As Wnt signalling pathways are complex, choosing the right target is challenging. The team at Duke-NUS Medical School found a way to shut down Wnt protein production via a single mechanism. They chose to inhibit the activity of an enzyme called Porcupine (PORCN), which catalyses a process critical to the production of all Wnt proteins and subsequently, their transport to the plasma membrane.
The scientists found that the inhibition of PORCN stopped the production of Wnt proteins. Experiments using animal models provided further support for this approach – certain mouse tumours produced by excessive secretion of Wnt were found to regress with PORCN inhibition.
Discovery and Development of an Effective Drug
In partnership with the Experimental Therapeutics Centre at A*STAR, the team is developing a potent orally-available PORCN inhibitor. This small molecule drug candidate, designated ETC-159, blocks the secretion and activity of all Wnt proteins. This has been shown to be effective in multiple pre-clinical cancer models, including certain types of pancreatic and colorectal cancers. ETC-159 entered Phase 1 clinical trials in mid-2015 and the preliminary results are promising. A back-up molecule, designated as ETC-569, is also available.
Duke-NUS Medical School is looking to co-develop with or out-license ETC-159 to a suitable industry partner.