What's in a Name?

By Any Other Name....WWTR1=TAZ, and Why That's Important. You may know that Brian Rubin, an acclaimed, first-rate molecular pathologist at Cleveland Clinic and the key scientific researcher in EHE discovered a few years ago that the genetic alteration underlying EHE is a 'fusion' of two genes: WWTR1 and CAMTA1. Til now, there's been very little interest in the basic science community to do research on EHE because it is so rare.  However, I believe that will change soon. It turns out that WWTR1 has another name: TAZ. So, just to this clear up WWTR1=TAZ but there is another (entirely different) gene called TAZ (http://en.wikipedia.org/wiki/Tafazzin) so the TAZ that is altered in EHE is sometimes called YAP/TAZ to avoid confusion since those two genes (YAP and TAZ) are very similar highly conserved paralogues that both promote cell growth and are normally inhibited by the Hippo signaling pathway. Note the recent publications showing that fusion in YAP can also cause EHE. So, abnormal cell growth in EHE occurs because the fusion protein is not inhibited by Hippo and therefore continually signals for cell growth to occur. OK, enough background. 

Significance of TAZ The little lesson in nomenclature is important because TAZ is now becoming a highly researched gene since mutations in it are found at very high rates in common cancers (e.g breast). I expect that EHE should no longer be the super rare thing no one wants to study. My hope is that we can bring TAZ people over to EHE and I've been focusing on this for the past several months. It's definitely new hope since it appears that big Pharmas are now assembling TAZ teams to find targeted drugs. Also TAZ knock out mice aren't really very sick, meaningTAZ  inhibition shouldn't be too adverse for patients (hopefully). 

Upstream and Downstream Targets. There are two theoretical ways to inhibit activity of the mutant TAZ in EHE.  TAZ is a transducer for Hippo, but it also responds to a number of other important signals: Wnt, f-actin, mevalonate, etc. If the problem wiht the fusion is that the TAZ signal becomes perpetually active will it be sensitive or insensitive to alterations in upstream signals. Some people think the fusion will remain active no matter what. I think (believe, hope) that inhibiting upstream activators could reduce activity of the fusion. This is important since there are many drugs available now that target these upstream signals. However, if inhibiting these upstream signals don't change TAZ activity there's still the possibility that we can discover drugs that inhibit activity downstream of TAZ where it promotes cell growth by interaction with DNA. 

What We Need Now: Cell and animal models will allow us to screen for and test drugs (upstream or down) that could treat EHE. So, developing such models is a VERY HIGH PRIORITY for us. Could one of the drugs already on the shelf be 'the one'? Won't know til we get a cell or animal model.