"Dream Team" Leader Looks First to Existing Drugs in Exploring Epigenetic Therapies

Published: Tuesday, Nov 12, 2013
Ramesh K. Ramanathan

Stephen B. Baylin, MD

 

Deputy Director
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins Medicine
Baltimore, MD

Stephen B. Baylin, MD, is conducting research in his laboratory at Johns Hopkins Medicine that aims to bring epigenetic therapy to the forefront of cancer management, in particular in gaining a better understanding of the abnormalities of chromatin and DNA methylation that may account for the development of epigenetic abnormalities during tumor development.

Baylin, who is the Virginia and D.K. Ludwig Professor of Oncology and Medicine, chief of the Cancer Biology Division, and associate director for Research at Hopkins, has received numerous awards and coauthored more than 350 peer-reviewed publications. Along with Peter A. Jones, PhD, DSc, at the University of Southern California, he leads the Stand Up To Cancer Epigenetics Dream Team.

1. Please briefly describe the research in your laboratory as it relates to epigenetic changes in cancer.

For several decades, we have been trying to determine how an epigenetic alteration can play a principal role in the initiation or progression of cancer. Essentially, we are attempting to understand the molecular processes that drive it, how it evolves over the course of a cancer, and, if we reverse the process, how it would give us new and better ways to manage cancer.

2. How do epigenetic modifications contribute to cancer development?

I like to make the analogy that your DNA is the hard drive, upon which all the information needed to instruct every single cell in your body to do what it needs to do is written. It can direct normal, healthy processes and, if it is damaged, it can govern abnormal processes that contribute to the development of disease. But a hard drive without software does not know how to play out its potential. The functions of the DNA are determined by which genes are active or inactive at any one time and by certain structural aspects of the DNA, both of which require the software. One of the principal software packages is epigenetics. It’s an oversimplification, obviously, but I think it is an effective analogy.

The way that this software package works is that we wrap our DNA up very tightly around protein structures (laid out flat, the DNA in any given cell would spread out a long way). How tightly or loosely you wrap the DNA determines how it functions. This is a complex process that involves how you move the proteins around and how you modify them. It also involves the biochemical modification of the DNA itself—a process called DNA methylation. Essentially, anything that goes wrong with the hard drive can also go wrong with the software in cancer and there is a delicate balance to these modifications. A building enterprise has developed to understand all the epigenetic abnormalities that we now know are present in the cell and their role in cancer.

DNA methylation was the earliest identified epigenetic change. It occurs all over the DNA, but one of the regions we focus on is where gene regions start and sites within these which are one key determinant whether the gene is switched on or off. About half of the genes in our body don’t have DNA methylation in and around these sites, as they need to be active or be ready to be activated. In tumors, even single ones in an individual patient, anywhere from 50 to several hundred genes have methylation at these sites when they shouldn’t. This can shut down genes inappropriately and, if this happens for a gene that is preventing the development of cancer (a tumor suppressor gene), it can help drive cancer formation. It has the same outcome as damage to the hard drive, but in this case the hard drive is still functioning underneath.

We are trying to figure out which genes are involved in these epigenetic processes and, if you could put the software package back in an appropriately functioning state, whether this could offer a therapeutic strategy for cancer. There are old drugs, which used to be toxic, but at lower doses will reverse the methylation of DNA. My colleague, Peter Jones, with whom I work closely, discovered the action of these drugs. They make it a possibility that we could reverse inappropriate methylation and, at low enough doses, they could be specific for these processes while not generally toxic to cells, and could be added to the management of common tumors. Ultimately that’s where we would like the field to go.

3. Which are the most promising epigenetic-targeting drugs currently under development?


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