Mesothelioma and the tumour suppressor gene, NF2

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Published: 15 May 2013
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Dr Emanuela Felley-Bosco – University Hospital Zurich, Switzerland

Dr Emanuela Felley-Bosco talks with ecancer at EMCTO 2013 in Lugano, Switzerland about the difficulties of treating mesothelioma.

NF2 is the tumour suppressor gene most abundant in mesotheleoma; however there are a number of difficulties in targeting this mutation. Mesothelioma is often associated with exposure to asbestos fibers and leads to continuous tissue damage. Due to the problems in targeting NF2, Dr Felly-Bosco explains how researchers are trying to circumvent this by targeting other stimuli that make the tumour cells to proliferate.

European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2013

Mesothelioma and the tumour suppressor gene, NF2

Dr Emanuela Felley-Bosco – University Hospital Zurich, Switzerland

Emanuela, mesothelioma is a difficult disease but you’ve got some insights into the molecular characteristics of it, you’ve been talking about them here. Let me go straight for one of the targets you’re looking at, NF2, could you tell me about that and then I’d like to ask you about what it is that makes life so difficult in treating mesothelioma. But you’re doing research on NF2, tell me all about that please.

NF2 is one of the tumour suppressor genes that is most abundantly mutated in mesothelioma. Basically it’s a negative break like most tumour suppressor genes and is active when you want to do tissue repair. As you may know, mesothelioma is associated with an exposure to asbestos fibre and this asbestos fibre accumulates in the pleural space and this leads to continuous tissue damage. So the tissue copes by stimulating repair and unfortunately when you have chronic damage an oncogenic event, and this oncogenic event, happens, disrupting this negative break.

And is NF2 something that you can target?

This is the problem. When you have a tumour suppressor gene unfortunately it’s very difficult to target them so you can find other ways. For example, what we did in our laboratory is to try to circumvent that by targeting what are the stimuli that are going to make the cells proliferate and this is mostly what are the developmental pathways that are reactivated during chronic tissue repair.

So is NF2 giving you insights into that?

NF2 is giving us insight. NF2 has also insight in, of course, this persistent stimulation where it is attacked as a negative break. But there are also other very interesting observations where, for example, if you express or not a wild-type, as we say, NF2, you might be sensitive to a drug in the mTOR pathway, this is the famous PI3 kinase pathway. Therefore, if you do not have this NF2 you might be more sensitive to this type of drug. Of course, this has not been yet tested in a clinical trial but we hope that we will be able to do that in the near future.

There’s a lot of interest in PI3 kinase in many branches of cancer but another fairly familiar name is BRCA and you’ve got BAP1, which is a BRCA associated protein. What’s happening there?

This is also quite interesting because indeed, as you said, BAP1 is BRCA associated protein 1 and has been found in a screen for proteins that are associated with BRCA1 but apparently has nothing to do to DNA repair as BRCA1 is. It’s mostly associated with chromatin remodelling. What is particularly important for BAP1 is that there are germline mutations that seem to predispose to several cancers including mesothelioma. So here now we have maybe not only a driver gene but also a modifier gene and this might be quite important.

Again, does this lead to a pathway that you could inhibit or do something about?

I think that for BAP1 we’re still trying to understand how it acts as the chromatin level. So the chromatin is the structure of the DNA and the structure of the DNA is quite important because it depends: if it’s open you can have expression of genes whilst if it’s closed you do not have expression of genes. I think that we need to understand better the function of BAP1.

With BAP1 and also with NF2 how far down the line have you got towards treating patients?

We have to say that there are clinical trials targeting the mTOR pathway but for the moment they are not stratifying the patient for NF2 wild-type of mutation. What is a very important point is that it seems that for NF2 what is important functionally is the nuclear localisation of this NF2 protein. Unfortunately for the moment it’s been dramatically difficult to assess the nuclear presence of NF2 because of technical issues.

Now very briefly can you tell me about dynamics of the tumour too because which cells are cycling makes a difference, doesn’t it?

It does. Basically we heard during our meeting about the tumour heterogeneity at the molecular level However, I would consider also dynamic heterogeneity in the sense that in mesothelioma the median proliferating index that are the cells that are cycling at any time, it’s about 10%. So with cell cycle targeting chemotherapy which is the actual therapy, cisplatin-pemetrexed that is the classical chemotherapy, we are targeting cell cycles. So you see that at a certain point we will destroy just a small part of a tumour.

So one tenth?

One tenth of the tumour.

So to sum it up, what then is the hope that with these molecular insights you will be able to improve therapy for mesothelioma? What hope would you hold out for cancer doctors?

I think that there would be one chance if, for example, try to tackle the problem of the quiescent cells and maybe make them go really out of the cell cycle. Hopefully what we aim to is to make them recognised by the immune system and maybe there is a place also still for chemotherapy because, as we know…

It’s knowing where to use it and when.

Exactly, exactly.

And then with BAP1 and NF2, in just a couple of words, what hope do they hold out?

As we said, for the mTOR pathway it would be good to be able to stratify the patient for NF2 and for BAP1 to really understand what is the prevalence of this germline mutation in mesothelioma, sporadic cancer. This is not known yet.

But do you feel we are going some considerable way down the path of understanding these processes?

Hopefully, yes.

Thank you very much.

Thank you.