ASH 2015

Using epigenetics to manipulate cancer cells

Dr Stephen Nimer - Sylvester Comprehensive Cancer, Miami, USA

We hear a lot about genetics but in hematologic malignancy we’re not always hearing about epigenetics. But you happen to think this is a very important question, why?

Well, first of all if you look at the genetics of many of the myeloid diseases they’re actually mutations occurring very commonly in epigenetic enzymes and genes. For instance, DNMT3A, ASXL1, TAT2, they’re seen not only in disease but even in what’s referred to as clonal haematopoiesis of elderly and aging. So these are very common mutations and it suggests that the pathway, meaning aberrant epigenetics, is really critical in cancer.

Could you define epigenetic changes, then? Because these are not the same thing as you get from your mum and dad.

Right. I think there are two easy ways to think about this. One is the notion that every cell in your body has exactly the same DNA but each cell in your body has its own function and its own identity. So to maintain the cellular identity requires epigenetics. You could see the same principle applying to a cancer cell; a cancer cell, every time it divides, must maintain its identity as a cancer cell. So if you can interfere with the epigenetics of the process you can get a cancer cell to behave like a normal cell and acquire normal functions.

So you can dress a wolf in sheep’s clothing, basically?

Exactly. You can take a cell that had no function with a specific mutation and then, even though the mutation is still there, suddenly the cell can function as a neutrophil or as a red blood cell or a platelet.

And epigenetic functions partly come from the environment or the surrounding ambiance.

That’s a very good point, which is when your cells respond to something in the environment they don’t change the DNA, the DNA is fixed. But in order for the cell to respond requires an epigenetic response so even your diet, the role of inflammation and aging, these all affect the epigenetics of the cell because they don’t have a specific impact on the DNA.

What could doctors potentially be doing to influence the epigenetics of their patients positively so that they don’t get cancer or so they recover from their cancer?

There are some interesting things about diet, methionine…

Like?

So whether you should have methionine or less methionine, valine, less valine, more valine and the sirtuins are a group of histone deacetylases and they’re involved in aging. Activating these enzymes is something that red wine does, resveratrol, and so there’s a notion that some of the same things that may prevent aging may also prevent the mutations that occur in an epigenetic manner.

Now, there haven’t been big studies done on this, double blind controlled, placebo controlled studies, but what evidence is there that you would label as scientific about some of the epigenetic factors that could potentially be targeted in cancer?

There are now some drugs, the IDH mutants are targeted by an IDH inhibitor, EZH2 mutants targeted by an EZH2 inhibitor. So there are a variety of enzymes that are very important in self-renewal or involved in the differentiation process for cancer cells and those are at the top of our list for targeting with small molecules because these are enzymes and so they are targetable.

And do they mix well with other treatments?

One of the very exciting things is we learnt how to boost the immune system so that it can better recognise the cancer cell, is that there are ways to make the cancer cell more recognisable to the immune system. One of those is checkpoint blockade – those inhibitors basically remove the camouflage from the cancer cell and allow the immune system to see it. But epigenetics can also allow gene products to suddenly be expressed for the first time on the cancer cell and those very gene products can be the target of immunotherapies. So we’re very excited about combining epigenetic therapies with immunotherapy.

Now, bearing in mind the fact that epigenetics is not something that most cancer doctors are thinking about every day, how would you summarise what doctors should take away about this topic from the perspective here at the American Society of Haematology meeting?

The first principle would be cancer cannot simply be thought of as a genetic disease anymore; it’s a genetic and an epigenetic disease. The second thing is that these are targetable. We’ve been trying to get targets in the cell and now that we have enzymes that are easy to target, the future, probably the next decade, we’re going to see the introduction of a large number of drugs that can target epigenetics.