Ann Boija: “Beta catenin condensates as central nodes of dysfunction in Wnt-driven cancers”

[Transcript]

Current treatments are optimized against a single target, but that target is seldom driving the disease on its own, especially in cancer, so you’re only targeting part of the problem. If you’re targeting the entire disease driving process, we have opportunities and the potential to have a more transformative effect by hitting all of those components that are required to drive the disease.

Beta catenin and many other transcription factors are, that are key to drive many malignancies, have a high degree of disorder, and disorder means that the structures of the proteins almost like noodles or spaghetti, are taking many different confirmations. So, it’s really hard to develop a drug that binds to a specific site. They don’t have any clear binding pockets on these proteins, and we are not able to crystallize them to really understand the structure of the protein. So, instead of going after that specific target, we are now going after the condensate, we are in the disease driving target node. We’re not saying that we absolutely need to target and bind that specific protein, we’re targeting the condensate wherein it resides. We have a new way to drug these kind of undruggable factors that are hugely disordered. Broadly for drug discovery, this really opens up the target space, so we can now go after a larger portion of the proteome. Where we have been kind of limited to those structure regions of the proteome, we can now go after the full proteome in this new way of targeting these disordered proteins, which we know are absolutely key to drive many diseases.

A condensate is an integrated node of several different disease pathways. By targeting this node, we can begin to develop drugs that are applicable to a large genetic population within a specific cancer, but also applicable to additional cancers outside of this. Beta catenin is a complex signaling pathway, with many factors, which converged upon a beta catenin condensate. In traditional drug discovery, you would need to target each of those factors for a specific genetic population, while here, it doesn’t matter where you have an aberrant mutation in the pathway, because it’s all converging upon this condensate. And by not going after those individual mutant proteins, but going after the node of all of those factors, you will be able to capture all of those genetic populations and have a more transformative effect.