Pharma Strategy Blog

Recently, epigenetics has been very much to the forefront with promising new human data in lung and breast cancers.

Nature Medicine

This morning I was therefore thrilled to see some exciting work just published in Nature Medicine Online First from Ray DuBois’s lab at MD Anderson Cancer Center, on the potential role of inflammation and silencing of tumour suppressor genes in early colorectal cancer. Previously, the group looked at the role of COX-2 in intestinal inflammation and colorectal cancer and observed that:

“A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC.”

Epigenetics is rapidly becoming a crucial and fascinating field of research. Dr DuBois kindly provided an easily understood explanation:

Epigenetics is defined as “the study of heritable changes in genome function that occur without a change in DNA sequence.”

One of the things that many people have trouble with is grasping the difference between mutations (genetic changes) and methylation (epigenetics). I loved Dr DuBois’s quote from Thomas Jenuwein, an epigenetics expert in Vienna:

“The difference between genetics and epigenetics can be compared to the difference between writing and reading a book.  Once a book is written the text (genes or DNA sequence) will be the same in all copies distributed to the audience.  However, each individual reader of a book may interpret the story slightly differently, with varying emotions and projections…

In a similar manner, epigenetics would allow different interpretations of a fixed template and result in different read-outs dependent on the variable conditions under which the template is interrogated.”

 

What did the current research show?

In a succinct article, Xia et al., (2012) clearly demonstrated that:

1. PGE2 promotes intestinal adenoma growth by silencing certain tumor-suppressor and DNA-repair genes.
2. This process took place through the induction of DNMT1 and DNMT3B specifically.

This research is, however, the first time the connection between inflammation and epigenetic changes has actually been demonstrated scientifically, as Dr DuBois noted:

“This is the first time I know of that there has been such a clear molecular connection between the two, with clear cut effects on the pathway and how it has an effect on the downstream. We never expected the effects on some of the tumor suppressors and mismatch repair genes. That was pretty exciting when we found that effect.”

What was particularly interesting, though, is that they also showed that it might be possible to tackle these issues using an anti-inflammatory drug (celecoxib) and/or a methylating agent (azacitadine). Both of these drugs reduced the size and number of tumours in mice with colorectal cancer in their experiments. In addition, the best responses occurred when both drugs were used together, suggesting a powerful additive effect coud be achieved.

What are the next potential steps from this research?

Obviously finding the link between inflammation and epigenetic changes is important, but there is much work that still needs to be done. Dr DuBois laid out some important next steps:

“Ultimately, what needs to be done is that we need to map out the whole epigenome now under a variety of situations where we apply an inflammatory stimulus or change the state of inflammation because I think it is really telling us something about the underlying mechanisms there.”

We already know from existing research that there is infiltration of immune cells into the tumour microenvironment, and in some situations, that can stimulate the cancer to progress faster:

“One of the ideas that is emerging is that the intestine, especially the large intestine, is in a special niche where it has to respond to this microflora. If there is any breach in the barrier, like adenomas or developing cancers, then that can bring inflammation directly to the tumor microenvironment because of all those bacterial products and other interactions between the microflora and epithelial cells.”

This research is just the beginning – ultimately, we need to think in terms of effective chemoprevention and treatment based on our understanding of the underlying biology:

“It was totally unexpected and I think it is going to lead to some things that will hopefully help, as we do more research, understand better how these interactions occur. Colorectal is a unique situation because it got all those bacteria in the lumen.

There have been some isolated reports about different types of bacteria causing problems, but this really could explain how the genetic somatic mutations interact with the local environment in the colon. We will have to think about ways to intervene to try to prevent or treat the disease more effectively.”

From a clinical standpoint, an obvious follow-on from this research would be to consider a clinical trial for patients who are at extremely high risk for developing colorectal cancer, such as those with a genetic predisposition, to see if combination treatment with these two classes agents (anti-inflammatory and methylating agent or HDAC) would decrease their subsequent risk of developing colorectal cancer.

All in all, some very exciting research to kick off this week and well worth reading.

References:

Wang, D., & DuBois, R. (2009). The role of COX-2 in intestinal inflammation and colorectal cancer Oncogene, 29 (6), 781-788 DOI: 10.1038/onc.2009.421

Xia, D., Wang, D., Kim, S., Katoh, H., & DuBois, R. (2012). Prostaglandin E2 promotes intestinal tumor growth via DNA methylation Nature Medicine DOI: 10.1038/nm.2608