The European Association for Cancer Research, 7-10 July 2012, Barcelona, Spain

Epigenetics of cancer and changes in DNA modification in tumours

Professor Manel Esteller – University of Barcelona, Catalonia, Spain

Can you tell me about what you’re presenting today?

I’m going to present a little bit about our efforts in epigenomics of cancer, trying to see at a lower level the changes in DNA methylation, histone modifications in tumours. This is very important because it’s clear that cancer is not only an accumulation of mutations but also an accumulation of defects in epigenetics like DNA methylation.

Why is this important potentially?

This is important for a couple of reasons at least. One is that epigenetics is providing biomarkers of disease, of prognosis and of response to chemotherapy. That’s one of several examples like MGMT methylation and response to Temodal in gliomas and BRCA1 methylation and response to PARP inhibitors in breast cancer. The second reason is that epigenetics is also providing targets for drugs so there are new drugs approved already for leukaemia and lymphoma, that they target epigenetics and  hopefully they’re going to be extended to epithelial tumours.

Can you give me some examples of these new drugs?

The drugs that right now are being used are drugs that are inhibitors of DNA methylation and inhibitors of histone deacetylation. But coming in the next months and in a couple of years, I’m sure there are going to be approved drugs that target histone methylation, for example, or histone demethylation. This is particularly important for subtypes of leukaemia and sarcomas.

How does this targeting work for histone methylation?

Histone methylation, it is critical that there are some fissures, there are some translocations that they involve histone modifiers. The system modifiers with histone methyl transferase are out there so we can target this with particular drugs. This histone methylation also contributes to cancer because it silences many tumour suppressor genes.

What other types of tumour are we going to be looking at?

In fact, epigenetic alterations are present everywhere. All tumour types have a component that is genetic alteration and a component of epigenetic alteration. The basic research so far has been done in leukaemias and lymphomas because probably they’re easy to study just following the blood, the markers, but there is a growing interest, for example, in colorectal tumours and in breast tumours and also in other small cell lung tumours. In fact, in the field of lung cancer we have just finished a very large study including 500 tumours trying to find a profile of DNA methylation, they give you a prognostic value in stage 1 patients.

So is it likely that with these new types of drugs they’re going to be able to apply to all different types of tumours?

There is no reason to believe that there are tumours that are resistant to these drugs. It’s clear that these drugs themselves, they are not the solution for many tumours but they are going to be part of the arsenal that we’ll have against these tumours. There are also some patients that are very sensitive to these drugs because they have some genetic or epigenetic alteration that is like an Achilles heel that you can hit back these tumours because they’re extremely sensitive to these small agents. Until now all the epigenetic drug are given, you have a given tumour in a given stage, you’re given this drug. It is clear now that we are going in detail to study the nature of these tumours, the biology and looking for the effects that make the cells more sensitive to drugs. For example, we have found a mutation in a histone modifier in small cell lung tumours that makes these tumours more sensitive to a particular inhibitor of histone deacetylation; this is the way to go, not only in epigenetics also of course in genetics.

What about side effects?

Side effects, it’s an interesting question because most of these drugs that we have right now, they are non-specific so they work the machinery of epigenetics and you can think that it can generate a lot of side effects but in fact in the patients they have very little side effects. This is probably due to patients, they are resistant to these drugs but the tumours are not. The tumours depend on this DNA methylation, histone modification levels, that they are addicted to this particular level of methylation or acetylation while normal cells are able to resist these drugs. At the same time it’s important to keep in mind that these drugs are given at very low dose; we’re not looking here for a shot, we’re looking to deliver something but modulates these tumours and make them grow slower.

So what were the conclusions of your talk?

The conclusion is that epigenomics, the use omics in the case of genetics is providing interesting targets for new therapies and most of all it’s also providing good biomarkers. Good biomarkers of diagnosis of tumours, of prognosis, of these malignancies and also markers that predict response to other chemotherapy agents, not only epigenetics but also agents that damage DNA, for example.

Thank you very much.