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.