New epigenetic targets and the role of DNA methylation fingerprints in cancer treatment

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Published: 26 Oct 2011
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Prof Manuel Esteller - University of Barcelona, Catalonia, Spain

Only ten per cent of DNA is used to create proteins but the remaining ninety per cent could potentially be used as a target for future therapeutic agents. Prof. Manuel Esteller explains how epigenetics can be used to target areas of non-coding DNA and reverse the silencing of tumour supressing genes. An example of these potential new treatment agents may have been found in early stage research into low dose therapy with enoxacin. This antibiotic has traditionally been used to treat urinary tract infections but has recently been shown to inhibit tumour growth in vitro and in mouse models.

Prof. Esteller discusses his research into the use of DNA methylation fingerprints in cancer therapy. We have seen promising results of early research into kits which use these fingerprints to help clinicians diagnose tumours of unknown primary origin. If successful, this technology will help oncologists identify the best course of treatment for metastatic cancers. Prof. Esteller concludes by outlining the next stage of his research which will look at developing a way to predict patient response to chemotherapy from DNA methylation fingerprints.

European Multidisciplinary Cancer Congress (EMCC) 2011, 23-27 September, Stockholm

New epigenetic targets and the role of DNA methylation fingerprints in cancer treatment

Professor Manuel Esteller – University of Barcelona, Catalonia, Spain

Professor Esteller, nice to see you again. How are you?

It’s a pleasure to be here.

You’re good?

Yes, I am.

What’s your story at this meeting? You pop up at all the meetings, what are you telling us in ECCO?

Here what I’m going to tell a little bit is all this weird DNA that does not originate proteins but does other stuff in cells, non-coding DNA. This looks to be very far away from the oncologists but in fact there have started to be small drugs that can target this weird DNA, this dark genome.

Start again. So you’ve got this little bit of DNA, you call it weird?

Yes, I call it weird DNA. So our DNA, this 10% generates proteins and all the mutations you are seeing, they are targeted in this DNA. But there is a remaining DNA that’s really important for functions in the cell that is also going to be a target of new drugs in the future. We are starting just to see the tip of this iceberg in these drugs.

So why should it be a target? Is it different in cancer cells?

Yes, it is different in cancer cells. Some of this is silence, it’s not expressed, and some of this is already mutated. So you have mutations that gain a function and lose a function; a similar story as the classical genes.

You’re a great silencer of DNA, having been an epigenetics leader in the field for a long time, is the silencing done in an epigenetic fashion?

Yes. There is silencing of many important tumour suppressors that is done by this epigenetic mechanism. The good news is that there are drugs that are able to revert that silencing, that are able to awaken these sleeping genes.

And this weird DNA. Give me a drug, I probably wouldn’t know, which drugs have you got?

There is a drug that is called enoxacin and this was an old antibiotic, an antibiotic used in renal infections. But here we have realised that this drug at a different, low dose is able to stimulate, to enhance, the production of these microarrays that they have a growth inhibitory function.

And it works in the test tube?

It works in the test tube.

It works in mice?

It works in mice and of course now we have to deal with all the patent stories…

There is no patent?

No, there is no patent, it ran out obviously but other molecules that can be derived from this molecule maybe will have an interest for pharma.

OK, because they’re not going to buy something that has no patent. On the other hand, it’s cheap.

It’s cheap, yes. It’s cheap, it works. It works, as you said, in the tube, in the cell culture, in the animal, now it has to see if it can work in humans. Clinical trials can be easily designed because we know the safety of this drug, it has been used like antibiotics so we know how it works in humans.

So you’ve started?

We have at least engaged some clinicians in how to design the study.

Because it’s going to be different, the design, isn’t it?

Yes, it’s going to be different. There is another part of the study, not here, that I think is going to be something useful is that we have also designed like a kit to make a diagnosis of tumours of unknown primary. These are something that I think are going to be a lot of use for many oncologists.

What’s the basis of the kit?

Here we take like a picture of the sample that we don’t know where it came from, it’s a metastasis most of the time so we don’t know where it came from and we look at this picture and say, ‘This picture looks like the picture of DNA methylation of a breast cancer,’ or like a picture of a colon cancer. We put together back to the right tumour and this, at least, will try to give a chance to these patients because now they can receive the right treatment for a breast or colon or a non-small cell lung cancer.

Are the differences that obvious?

Yes, the differences are very obvious. It’s like a picture of different people and you can match, saying ‘This has blonde hair, this has dark hair.’

The Barcelona ones and these are the Madrid variety.

Yes, you can make these pictures and separate tumours by the profile of DNA methylation. We call it DNA methylation fingerprint.

Fantastic. When is that going into the clinic?

I don’t know but here the brilliant thing is that already biotech companies have taken this idea and they’re pushing forward and I think that this one of our discoveries that can reach a market and the patients sooner than others. It’s easier to test than drugs and cheaper to design the trials.

And the testing is much less rigorous.

Yes, and here you can compare it with other tests in the market. So I think it’s something that can be very useful.

Good stuff. That’s absolutely fantastically interesting. You’re going to present where and what next? What’s the next experiment?

The next experiment that we are doing, in the same way that we can obtain a DNA methylation fingerprint to say this is a colon cancer, this is a breast cancer, we intend to make a chemotherapy predictor. It’s like a DNA methylation fingerprint for response to drugs. So we have the sample of DNA, we run the sample through a predictor DNA methylation and we give a list of drugs that are most sensitive to this particular DNA or this particular sample. And we can test this later in mice where you have the primary tumour transplanted. So you have something that, not only according to epigenetic creates something that is able to give a response but also when we put this drug in the mice it will give another response.

If that comes off, that will be fantastic.

Yes, I think so. The proof of principle we’re trying in pancreatic cancer, as you know, because this is a tumour with very poor prognosis.

It responds to almost nothing.

Almost nothing so even a little response, we’ll see something that we’re able to validate.

Thank you very much again for coming and telling us what’s happening in your lab.

It has been a pleasure to be here and I’m happy to contribute to this excellent meeting.