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Targeting Cancer Epigenetics

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MD Anderson Cancer Center's Jean-Pierre Issa targets epigenetic pathways in cancer treatment. His work contributed to the development of one FDA-approved drug for the treatment of myelodysplastic syndromes that target the DNA methylation pathway, and he is continuing to evaluate other pathways for potential drug candidates to treat MDS and other types of leukemias, such as acute myelogenous leukemia. Issa recently spoke with Monica Heger for Genome Technology about his current work, as well as the future of his research, in targeting epigenetic pathways to treat other cancers.

Genome Technology: Why is the epigenome especially important when it comes to studies of cancer?

Jean-Pierre Issa: Cancer is as much an epigenetic disease as a genetic disease. This realization came from about two decades of work that showed a very high degree of epigenetic abnormalities in cancer, and separately, from very compelling data from animal models and in vitro cell line data that showed you can reverse the cancer phenotype by epigenetic manipulation with drugs. So this suggested that maybe we could treat cancer by reversing epigenetic changes. And that's what we've been trying to do.

GT: What are you focusing on right now in your research?

JPI: We recognize three major epigenetic pathways — DNA methylation, histone acetylation, and histone methylation or demethylation. We've focused on all these epigenetic abnormalities. DNA methylation is the one where we now have drugs. We've also done a number of clinical trials with histone deacetylase inhibitors. And in the histone methylation pathway there is a group of proteins referred to as the polycomb group of proteins, and one in particular is called EZH2. It turns out that the expression of these proteins is high in cancer, and they promote growth and metastasis.

There is some early evidence that inhibiting EZH2 function would markedly reduce tumorigenesis in various models. So there's a lot of activity right now in trying to develop drugs that work along that particular pathway, and it's one that I'm particularly interested in.

GT: What are the next steps of your research?

JPI: The first is to try and capitalize on what we've learned and try to extend it to other diseases. There's really no particular reason why the kind of leukemias we treat should be the only diseases that respond to [epigenetic] therapy. So there have been a number of efforts to try and bring this approach to other diseases, including solid tumors. We are running trials in things like lung cancer and colon cancer and hopefully breast cancer.

Another direction is to try to optimize the therapy and to overcome resistance. We are looking at combining approved drugs. We're looking at different schedules — using [the drugs] a little bit differently to see if we can optimize them, and also combining them with standard-of-care approaches.

And the third approach, which is really a research approach, is that this provides a proof-of-principle for epigenetic modulation. Now there are efforts across many different companies and academic laboratories to find new drugs that work in similar pathways.

GT: What do you see as the future for epigenetics in cancer treatment?

JPI: Well, I think that it's very clear that these drugs are here to stay and that they're going to improve survival. I think we're going to find more diseases where they work either alone or in combination. I think that there's going to be a whole cadre of drugs that are going to be in the clinic in the next five to 10 years that will help improve survival.

Ultimately, these drugs will probably not be powerful enough to cure patients on their own. So I'm looking at a future where these drugs are used in combination or on an alternating schedule with chemotherapy to indeed achieve the goal of increasing cancer cures.

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