Wnt inhibition

Host: Owen Sansom, Cancer Research UK Beatson Institute


Room: Hall 1B

The Wnt signalling pathway is thought to be a key pathway for cancer development. Of all cancers, Colorectal Cancer is thought to be driven by activation of Wnt signalling (often by loss of the Apc tumour suppressor gene). However other cancers such as HCC (approximately 1/3) are commonly mutated for components in the pathway. This has led to the prediction that targeting Wnt signalling in these cancers may have a very beneficial effect. Consistent with this elegant studies by the Lowe laboratory have shown that restoration of APC levels in established tumours leads to tumour regression.

There are currently a number of preclinical Wnt inhibitors which target the Wnt signalling pathways at different levels. Blocking antibodies of receptors and ligand exist as do inhibitors which stop ligand secretion. Of these further in development are Porcupine inhibitors (e.g WNT974 Novartis) that have be used in early phase clinical trials). Excitement over the use of Wnt inhibitors has been raised that they may be efficacious in tumours that carry mutation in negative regulators of the pathways such as RNF43 or amplification in R-spondin and thus should remain responsive to ligand inhibition. However, mutations in other member of the pathway e.g. APC may lead to independence of ligands and hence other inhibitors have been developed to target the pathway downstream of the ligand (e.g. Tankyrase inhibitors, Bcl9-9l and b-catenin/CBP300 inhibitors).

One other major concern for Wnt inhibition is that given it is required for stem cell population in many organs it whether there will be toxicity in patients for long term administration and problem combining with other agents. This session will discuss the latest developments in Wnt signalling inhibition, the therapeutic window and the latest clinical developments.

Confirmed speakers:
Felipe de Sousa e Melo, Roche, USA
Mariann Bienz, MRC Laboratory of Molecular Biology, UK
Julian Blagg, The Institute of Cancer Research, London, UK

Targeting stem cells in colorectal cancer
WNT signalling and the Mediator complex associated kinases CDK8/19
Fixation and spread of somatic clones in adult human colon
R-spondin gain-of-function in colorectal cancer – a comparison between mature tumours and precursor polyps
Evaluating the potential of the Wnt enhanceosome scaffold BCL9/B9L as a therapeutic target in colorectal cancer