Lessons from mouse models of glioblastoma

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Published: 11 May 2018
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Dr Luis Parada - Memorial Sloan Kettering Cancer Center, New York, USA

Dr Parada speaks with ecancer at Cancer Research UK Brain Tumour Conference 2018 in London about new understandings in the genetic underpinnings of untreatable glioblastoma.

He describes the stem cell origins of the disease, and how single-cell sequencing has opened avenues in targeted treatments to attack quiescent cancer cells.

Dr Parada notes that these therapies come with very encouraging tolerability in mice, compared to the highly mutagenic chemotherapy regimens.
 

What I talked about was the use of genetically engineered mouse models to try to understand the origins of glioblastoma and to study the biological properties that are unique to this very fulminant tumour that is essentially untreatable. So we’ve tried to molecularly, genetically recapitulate the core mutations that cause these tumours in mice so that we get mice that spontaneously develop them. Of course in the mouse then you can start studying the very earliest phases of what goes wrong and where it goes wrong. That has led us to the model that, in fact, glioblastoma is a stem cell disease and that, in fact, most other cells in the brain are incapable of giving rise to glioblastoma.


So with that information we have then begun to study the transition of normal stem cells to glioblastoma stem cells. These are two needles in a haystack: stem cells are a needle in the normal brain haystack and cancer stem cells are a needle in the glioblastoma haystack. Those are the two things that need to be teased out to study their intrinsic properties and how one becomes the other.


So those are the tools that we use, the mouse models, but with that we’ve been able now to use modern genomic technology to do single cell isolation and sequencing. That has given us insights into the properties of these cells but also it has really led us to understanding that to therapeutically treat glioblastoma treating the highly dividing cancer cells, which is where most therapeutics focus and where most classic chemotherapeutic agents focus, is actually only part of the problem because there’s a quiescent stem cell in the tumour that is not targeted by these therapies because they weren’t designed for that. These therapies were designed to kill dividing cells. So based on that we have now begun a programme to develop targeting therapeutics for quiescent cells and I discussed some of our new developments which are quite exciting.


We are able to essentially block the growth of glioblastomas transplanted into mice. So we have drugs that don’t make the mice sick because they don’t target dividing cells by virtue of their cell division properties, they actually target cancer cells by virtue of unique properties of cancer cells that are not present in normal cells. In the early phases of what I’ve discussed, in mice the major sort of canary in the coal mine, if you will, is if mice are ill they go off their food and so they lose weight. We have been able to successfully impede the development of glioblastomas in mice in regimens of one month of daily treatment with these novel therapeutics and the mice don’t lose weight but the tumours don’t thrive. So we’re excited about that and really it brings out new principles about how to think about targeting cancer stem cells therefore identifying the true enemy, if you will.


It turns out that if you only target the proliferating component you’re going to have this quiescent stem cell that is going to give rise to a new proliferating component and on and on and on. So we really have to target both and the first step to being able to target the quiescent cell is acknowledging its existence and identifying its properties and that’s what we’re doing.


What’s the future for this study?


We have to continue studying these cancer stem cells and better understanding them and understanding the details of how normal stem cells transition to cancer stem cells. This is a whole new area of research and we like to think that we’re participants in the vanguard. So we hope to continue to do so and at the same time to try to continue to develop and understand how the compounds that we’ve identified kill cancer cells specifically.
Keep an open mind. Most classical compounds are mutagenic classical chemotherapies. They are a major, if not the sole, source of resistance. You’re giving a tumour really harsh mutagens to kill it and that’s fine and well but the cells that survive have acquired all sorts of new mutations and permitted a selection for resistance. So it’s important to keep an eye open for improved strategies.