The Epigenetics Revolution

The researchers at Columbia University and Memorial Sloan-Kettering who first developed SAHA patented it. They then set up a company called Aton Pharma to develop SAHA as a drug. In 2004, after promising early results in cutaneous T cell lymphoma, Aton Pharma was bought by the giant pharmaceutical company Merck for over $120 million dollars. Aton Pharma had almost certainly spent millions of dollars to get SAHA to this stage. Drug discovery and development is an expensive business. The two companies that marketed the DNMT1 inhibitors have been bought relatively recently by larger pharmaceutical companies, in deals that totalled about $3 billion each[191]. If a company has paid a huge amount of money to develop or buy in a new drug, it would much prefer not to carry on spending like a drunken sailor when it comes to clinical trials.

Naturally, it would be a big improvement if we could run clinical trials with a much better idea of which patients will benefit, rather than having to take pot luck. Unfortunately, most researchers agree that many of the animal models used to test cancer drugs are very limited in their capacity to predict the most susceptible human cancer. To be fair, this isn’t just true of cancer drugs targeted at epigenetic enzymes, it’s also true of pretty much all oncology drug discovery.

In an attempt to get around this problem, researchers in both academia and industry are now looking for the next generation of epigenetic targets in oncology. DNMT1 is a relatively broad-acting enzyme. DNA methylation is rather all or nothing – a CpG is methylated or it isn’t. HDACs tend to be pretty non-discriminating too. If they can get access to an acetylated lysine on a histone tail, they’ll take that acetyl group off. There are a lot of lysines on a histone tail – there are are seven on histone H3, just for starters. There are at least ten different HDAC enzymes that SAHA can inhibit. It’s quite likely that each of these ten can deacetylate any of the seven lysines on the H3 tail. This is hardly what we would call fine-tuning.

No easy wins

This is why the field is now moving in the direction of assessing different epigenetic enzymes, which are much more limited in their actions, to see which are important players in different cancers. The rationale is that it will be easier to understand the cellular biology of enzymes with quite limited actions, and this will make it easier to determine which patients are likely to respond best to which drugs.

The first problem in doing this is rather a daunting one. Which proteins should we investigate? There are probably at least a hundred enzymes that add or remove histone modifications (writers and erasers of the epigenetic code). There are probably as many proteins that read the epigenetic code. To make matters worse, many of these writers, erasers and readers interact with each other. How can we begin to identify the most promising candidates for new drug discovery programmes?

We don’t have any useful compounds like 5-azacytidine and SAHA to guide us, so we have to rely on our relatively incomplete knowledge in cancer and in epigenetics. One area that is proving useful is considering how histone and DNA modifications work in tandem.

The most heavily repressed areas of the genome have high levels of DNA methylation and are extremely compacted. The DNA has become very tightly wound up, and is exceptionally inaccessible to enzymes that transcribe genes. But it’s the question of how these regions become so heavily repressed that is really important. The model is shown in Figure 11.3.

^{Figure 11.3 Schematic to illustrate how different types of epigenetic modifications act together to create an increasingly repressed and tightly condensed chromosome region, making it very difficult for the cell to express genes from this region.}

In this model, there is a vicious cycle of events that results in the generation of a more and more repressed state. One of the predictions from this model is that repressive histone modifications attract DNA methyltransferases, which deposit DNA methylation near those histones. This methylation in turn attracts more repressive histone modifying enzymes, creating a self-perpetuating cycle that leads to an increasingly hostile region for gene expression.