"DIPG very, very closely resembles a normal glial precursor cell, called an oligodendrocytes precursor cell and that cell type, is the only cell type - the only glial cell type - that actually forms synapses with neurons. We've known this for the last twenty years although the field is still trying very hard to understand what it is these neuron-to-glial synapses do in the healthy brain. When we thought that perhaps DIPG cells and other high-grade glioma cells might be similarly forming synapses with neurons, that really would mean that the tumor cells are integrating into the neural circuitry and that brain activity could be providing really crucial electrochemical signals to the cancer cells. Now during brain development, these same kind of electrochemical signals-- changes in the voltage of the membrane --actually of the cells-- helps to promote normal neural stem cell development, and really contributes importantly to brain development and growth.
It would make sense for a glial malignancy of childhood to be hijacking these crucial mechanisms in normal brain development for their own purpose. So we wondered whether similarly synapses might be forming between neurons and glioma cells, neuron-glioma-synapses. We had a little bit of an early clue that this could be happening because a crucial growth factor that we had identified was up regulating the expression of a number of different synapse-related genes in DIPG cells and other high-grade glioma cells
We took a basic neuroscience approach to try to understand whether electro electrical synapses were actually forming between neurons and the glioma cells invading those circuits. What we found was that indeed, the gliomas like DIPG and other high-grade gliomas like glioblastoma, are synaptically integrating into the normal neural circuitry. If you want to think about this as a kind of a cybercriminal; this is a cell type that is actually hacking in to the neural infrastructure and deriving critical growth signals through this synaptic integration.
The first problem is to understand how and why it's happening and the second problem is to interrupt it. So we found that these synapses were forming between neurons and glioma cells and that the synaptic signaling was driving DIPG growth.
There's a particular kind of neurotransmitter receptor we found to be present in this neuron-to-glial synapses that that are present between neurons and DIPG cells and using an anti-epileptic drug that targets this kind of neurotransmitter receptor we found that that slowed DIPG growth.
So as we further study this and understand more of the molecular details, I think is going to show us a group of therapeutic targets that we hadn't appreciated that are really neurophysiological in nature and it may be that we can repurpose medicines that are normally meant for seizures, normally meant for migraine, or normally meant to treat cardiac arrhythmias, and instead use them to help us to slow the growth of DIPG and other gliomas.
As a clinician, understanding this integration of glial malignancies into neural circuits really helps to explain a couple of characteristics of the tumor that we knew to be true clinically but perhaps didn't understand. One of the important characteristics of glial malignancies is that they grow in the central nervous system. Now other cancers spread throughout the body and brain tumors, and in particular, gliomas really only ever grow in the central nervous system, despite the fact that the tumor cells we now know enter the bloodstream. They simply can't grow anywhere else. And this really helps to explain, for me, why that might be true; this micro-environmental interaction between the glioma cells and the central nervous system micro-environment is really critical and fundamental to glioma progression. Brain tumors only spread within the brain and it's because of this unique micro-environment of the nervous system.
The Cure Starts Now has supported my research program since the first day that I opened my lab. It’s been enormously important in helping us to develop new tools, in order to ask high-risk, high-reward questions and really to get the program launched.
This study, in particular, started when I won a Snap Grant Cure Fund. I proposed this crazy idea said I think that maybe DIPG is forming synapses with neurons and that matters and I pitched it in one of these four-minute sessions and walked away with a check to start the work and you know that's resulted and a great deal of additional funding as we gleaned more about this really fundamental question as we started to generate compelling data. But I would not have been able to get started without that funding."
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