Uncovering Epigenetic Targets in Cancer

Ahead of the American Association for Cancer Research annual meeting, being held April 14–18 in Chicago, Illinois, we spoke with Stephen Baylin, MD. Dr. Baylin is a professor of oncology and the co-director of the Cancer Biology Division and Associate Director for Research Programs of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland. He is a co-director of a Stand Up 2 Cancer-AACR team that is focused on epigenetic therapy for cancer, including combinations with immune checkpoint inhibitors. During the meeting, Dr. Baylin will be discussing the progress of epigenetics-based targeted therapy for cancer, in a presentation, “Probing Basic Understanding for the Potential for Epigenetic Therapy to Enhance the Efficacy of Immune Checkpoint Therapy.”

-Interviewed by Anna Azvolinsky

Cancer Network: Could you define what is meant by epigenetic therapy for cancer as opposed to other cancer treatment modalities that are approved and in development?

Dr. Baylin: Sure. Most other targeted therapies are pointed against genetic mutations which occur in the DNA of cancer cells. DNA is, in essence, like a hard drive. It contains all of the information to tell a wild-type cell-and, in many ways, a cancer cell-what to do. But like a hard drive, the DNA needs a software package to operate properly, and this software package has a major component that is called epigenetics, which means ‘above genetics.’

In a sense, epigenetics is the way we package our DNA; it is how the DNA is wrapped around proteins and packed into the cell in such a way that the cell knows which part of the DNA to use and which part not to use for gene expression. And just like the hard drive can go wrong, in the form of DNA mutations, even more so probably, epigenetics can be abnormally regulated in cancer cells, which tells genes to be overactive when they should not be. Or, as we often study, the dysregulation is in the form of genes losing function when they should be active.

The big difference here is that the genes lose their function without a genetic mutation, so the epigenetic changes are potentially reversible. Indeed, in the lab we have drugs in development to reverse these changes. So, epigenetic therapy refers to the use of these drugs to reverse and make certain gene functions that have been disrupted more like those in wild-type, noncancerous cells.

Cancer Network: What do we know about how epigenetic functions may be mutated or dysregulated in tumors? And are there specific tumor types where we know targeting epigenetic pathways may be most promising?

Dr. Baylin: In the last decade of studies, we’ve found that virtually every type of cancer, particularly the major, most common types of cancer, all harbor multiple epigenetic abnormalities. More and more, we are learning that those abnormalities are really part of what drives the start of cancer and the progression of cancer. So, in the end, all cancers harbor epigenetic abnormalities along with genetic abnormalities.

Cancer Network: Could you highlight examples of cancer drugs in development or that are approved which target epigenetic pathways?

Dr. Baylin: There are two classes of drugs which can target epigenetic abnormalities that are now approved by the Food and Drug Administration. For both of these classes, the drugs are approved in hematological malignancies. One class reverses abnormalities in DNA methylation. DNA methylation is one of the key signatures through which the cell regulates its epigenetic controls. That drug is approved in a pre-leukemia, a disease called myelodysplasia, which can turn into leukemia. Many patients with leukemia and myelodysplasia respond to this drug, called azacytidine, which can which can reverse DNA methylation abnormalities.

The second class of drugs is called histone deacetylase inhibitors, and these target a process that is closely aligned with DNA methylation wherein increases in DNA methylation at the start site of genes can inappropriately cause the genes to be repressed or nonactive. Inhibitors of these histone deacetylases, also called HDACs for short, relieve the abnormality and especially when these are used in conjunction with the drugs that target DNA methylation abnormalities. So, we often use these two drugs together.

Our charge now is to try to develop these drugs more for the common, solid tumors where these drugs have so far had less traction. Our Stand Up 2 Cancer team has major clinical trials testing azacytidine alone or azacytidine plus an HDAC inhibitor to see if these epigenetic therapies will work well in certain solid tumors.

Cancer Network: In your talk, you are planning to discuss possible strategies for combining epigenetic therapy with immune checkpoint inhibition, a type of immunotherapy that is now approved for many different solid tumors. What makes this a viable strategy, do you think? What is the rationale?

Dr. Baylin: One of the lead hopes for epigenetic therapy is that the two drugs I just mentioned may improve the efficacy of immune checkpoint therapy. This strategy came about 7 years ago when we noticed that, in a clinical trial for advanced non–small-cell lung cancer-which is our biggest killer among cancers, patients receiving a combination of azacytidine and an HDAC inhibitor had gone onto some of the first trials with immune checkpoint inhibitors for this lethal type of cancer.

And that small number of patients had tremendous responses to immune checkpoint therapy, raising the possibility that the epigenetic agents had somehow sensitized these patients to respond better to these immune checkpoint inhibitors, versus the possibility that it was just that these patients responded to the immune checkpoint inhibitor irrespective of their prior therapy.

Ever since that time, we have been trying to employ an epigenetic therapy plus the immune checkpoint inhibitor for lung cancer and other tumors, [to ascertain] whether we could understand whether the epigenetic therapy was indeed priming a response to the immune checkpoint inhibitor. We’ve been doing this in lung cancer, a progressive, advanced disease, and we’ve had to learn when to start the epigenetic therapy and how to time the therapy with these with the immune checkpoint inhibitor drugs to see if this is feasible.

In the meantime, at the end of 2017, we’ve developed much better ways to use the two epigenetic drugs together and found that they are very effective as antitumor agents in mouse models of non–small-cell lung cancer and ovarian cancer. When these drugs have antitumor effects in these models, they have profound effects on bringing in the proper immune cells into the tumor microenvironment, which then can prime the immune checkpoint inhibitor to work. So the promise is right up to the pivotal point, and if mice could prove to be like humans, these combinations may work in patients with cancer.

There are now ongoing clinical trials, many of which just started, to see if we can use this strategy for the management of human tumors, particularly for lung [cancers], bladder cancers, and hematological malignancies. Hopefully, over the next couple of years we will see if we can make clinical management changes for these diseases with these drug combinations.