It is important for EHEers to know the scientific goals that will allow us to tame or possibly cure this disease. This goal, our grail, is not out of reach given that the most important step has already been achieved: establishing the cause of EHE. We can even say that the second necessary step has also been taken: establishing how the underlying genetic alteration(s) in EHE cause cell transformation. Both steps were accomplished in Dr. Rubin’s lab and insofar as the EHE community supports his research, we can all pat ourselves on the back for helping him establish that mutations resulting in persistent activation of either YAP (~10%) or TAZ (~90%) and their resulting transcriptomes cause the proliferation of endothelial cells that we see as EHE. Sorry for the verbosity…… but what’s next?

We need at least 1) a cell model to screen and test drugs for their ability to suppress YAP/TAZ-driven expression; 2) an animal model of EHE to learn more about the disease and to test promising drugs identified in the screen and finally; 3) biomarkers of EHE to follow activity of the disease. So 3 is the magic number.

An example of 1) could be a cell system that allows high-throughput testing of drug effects on YAP/TAZ by computer analysis of immunofluorescence imaging (antibodies against that glow under a microscope). This could identify drugs that keep YAP/TAZ out of the nucleus (the only place they’re active) or that reduce mRNA levels resulting from YAP/TAZ binding of TEADs. Such systems have already been published and even identified drugs with possible activity against expression of the transcriptomes.  The only way we’ll know for sure if these drugs could alter EHE progression is by testing them in an animal model of EHE.  

The most workable animal model for EHE is a genetically engineered mouse (GEM). This is possible because EHE is caused by a single gene abnormality. Dr. Rubin is currently working on this project and is optimistic about having a good EHE GEM within the year. This would allow us to learn more about the biology of EHE, to test drugs against the disease and to test possible biomarkers. It’s exciting to contemplate now what treatments we might test in the EHE GEM. Keep thinking!

EHE is certainly a weird type of cancer. Unlike almost every other cancer, the extent of disease and number of organs involved are not good predictors of outcome. People live for long periods despite wide spread (or as we prefer to say, ‘systemic’) disease because it often remains dormant for years. The benefit of a biomarker is that we might use it to follow disease activity and thereby intervene at an early stage to suppress growth before the diseasebecomes clinically apparent or problematic. Possibilities include either a protein produced by YAP/TAZ activation, or EHE tumor cells or even EHE-specific DNA that could each be identified in a blood sample. The latter would allow so-called ‘precision medicine’ since it could be calibrated to identify only that DNA sequence specific to each patient’s mutation.

So, lots of good things to look forward to. Stay tuned.