The Epigenetics Revolution

Follow-on work showed that it’s not just DNA methylation that changes in cancer. There is also direct evidence for histone modifications leading to repression of tumour suppressor genes. For example, the histones associated with a tumour suppressor gene called ARHI had low levels of acetylation in breast cancer[183]. A similar relationship exists for the PER1 tumour suppressor in a form of lung cancer called non-small cell[184]. In both cases, there was a relationship between the levels of histone acetylation and the expression of the tumour suppressor – the lower the levels of acetylation, the lower the expression of the gene. Because these genes are both tumour suppressors, their decreased expression would mean that the cell would find it harder to put the brakes on proliferation.

This realisation – that tumour suppressor genes are often silenced by epigenetic mechanisms – has led to considerable excitement in the field, because this potentially creates a new way of treating cancer. If you can turn one or more tumour suppressor genes back on in cancer cells, there is a fighting chance of reining in the crazy proliferation rate of those cells. The runaway train may not run away quite so fast down the track.

When scientists thought that tumour suppressors were inactivated by mutations or deletions, we didn’t have many options for turning these genes back on. There are trials in progress to test if gene therapy can be used to achieve this. There may be circumstances where gene therapy will prove effective, but this is by no means certain. Gene therapy has struggled to deliver on the initial hopes for this technology, in all sorts of diseases. It can be very difficult to get the genes delivered into the right cells, and to get them to switch on when they are there. Even when we’re able to do this, we often find that the body gets rid of these extra genes, so any initial benefit is lost. There have also been relatively rare cases where the gene therapy itself has led to cancer, because it has had unexpected effects which have led to increased cell proliferation. The scientific community hasn’t given up hope for gene therapy and for some conditions it may yet prove to be the right approach[185]. But for diseases like cancer, where we would need to treat a lot of people, it’s expensive and difficult.

That’s why there is so much excitement about the development of epigenetic drugs to treat cancer. By definition, epigenetic changes do not alter the underlying DNA code. As we have seen, there are patients where one copy of a tumour suppressor has been silenced by the action of epigenetic enzymes. In these patients the code for the normal tumour suppressor protein has not been corrupted by mutation. So, for them there is the possibility that treatment with appropriate epigenetic drugs can reverse the abnormal pattern of DNA methylation or histone acetylation. If we can achieve this, the normal tumour suppressor gene will be switched back on, and this will help bring the cancer cells back under control.

Two drugs that inhibit the DNMT1 enzyme have been licensed for clinical use in cancer patients by the Food and Drug Administration (FDA) in the USA. These are 5-azacytidine (tradename Vidaza) and the closely related 2-aza-5′-deoxycytidine (tradename Dacogen). Two HDAC inhibitors have also been licensed. These are SAHA (tradename Zolinza), which we met earlier, and a molecule called romidepsin (tradename Istodax), which has a very different chemical structure from SAHA, but which also inhibits HDAC enzymes.

Following on from his successes in unravelling the molecular roles of 5-azacytidine, Peter Jones, along with Stephen Baylin and Jean-Pierre Issa, has played a hugely influential role in the last 30 years in moving this compound from the laboratory, all the way through clinical trials and finally to the licensed product. Victoria Richon played a major role in championing SAHA all the way through the same process.

The successful licensing of these four compounds against two different types of enzymes has given a major boost to the whole field of epigenetic therapies. But they have not proved to be universal wonder drugs, the silver bullets to treat all cancers.

Stop looking for miracles

That hasn’t been a surprise to anyone working in the fields of cancer research and treatment. There sometimes seems to be an obsessive determination on the part of certain journalists in the popular press to write about the cure for cancer. Generally speaking, scientists try to avoid being too dogmatic, but if there’s one thing most of them are agreed on, it’s that there will never be one single cure for cancer.