Dr Lamar’s research continues to make exciting progress

node leader
4 October 2020

We are pleased to be able to report that Dr Lamar’s team have been able to re-enter their lab and have been able to continue their research after a period of COVID lock-down. They have completed a mouse experiment using the NIH3T3-TAZ-CAMTA1 expressing cells and this shows definitively that TAZ-CAMTA1 renders the cells tumorigenic and metastatic.

We will now start to use this xenograft mouse model to test our candidate TAZ-CAMTA1 regulators. We can also label these cells so we can track their spread in the mouse (metastasis) and monitor tumor burden over time using an imaging device. So we can use this mouse model to test potential therapies. We also have a new in vitro (in a petri dish) assay optimized to test the ability of TAZ-CAMATA1 to render cells cancerous. This will allow us to rapidly test candidates, so we know which to focus on in the more expensive and time-consuming experiments in the mice.

They have also completed some additional work with the leading candidate (of the 6 proteins they identified) that appear to repress TAZ-CAMTA1 activity.

So far we know that if we overexpress this protein, called AMPK, we can repress TAZ-CAMATA1 activity. If we treat cells with a small molecule that is supposed to activate AMPK we see a moderate reduction in TAZ-CAMATA1 activity, but not as strong as if we over express AMPK. We are still trying to work out if this is because the small molecule does not effectively activate AMPK or if there is just not enough AMPK in these cells under normal conditions. We also found that the endogenous AMPK in these cells is repressing TAZ-CAMTA1, because if we inhibit AMPK the activity of TAZ-CAMATA1 goes up significantly. This is obviously not what we want therapeutically, but it is an important finding because it suggests that in these cells the existing AMPK pathway can regulate TAZ-CAMATA1, so if we can find a more effective way to activate this pathway or target another protein in the pathway, it may be a therapeutic approach for EHE.

We are very encouraged by these positive results and hope that the team will be able to find ways to activate these different pathways and so open up new ways to treat EHE. That will indeed be an exciting day.

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