Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (32 page)
Histone proteins are also found at the promoters of genes. Histone modifications can be very complex, as we saw in
Chapter 4
. But histone acetylation is the most straightforward in terms of its effects on gene expression. If the histones upstream of a gene are heavily acetylated, the gene is likely to be highly expressed. If the histones are lacking acetylation, the gene is likely to be switched off. Histone
de
acetylation is a repressive change. Histone deacetylases (HDACs) remove the acetyl groups from histone proteins and will therefore repress gene expression. By inhibiting these enzymes with SAHA, we can drive gene expression up.
Chapter 4
. But histone acetylation is the most straightforward in terms of its effects on gene expression. If the histones upstream of a gene are heavily acetylated, the gene is likely to be highly expressed. If the histones are lacking acetylation, the gene is likely to be switched off. Histone
de
acetylation is a repressive change. Histone deacetylases (HDACs) remove the acetyl groups from histone proteins and will therefore repress gene expression. By inhibiting these enzymes with SAHA, we can drive gene expression up.
So there is a consistent finding. Our two unrelated compounds, which control growth of cancer cells in culture and which have now been licensed for use in human treatment, inhibit epigenetic enzymes. In doing so, they both drive up gene expression which raises the obvious question of why this is useful for treating cancer. To understand this, we need to get to grips with some cancer biology.
Cancer biology 101
Cancer is the result of abnormal and uncontrolled proliferation of cells. Normally, the cells of our body divide and proliferate at exactly the right rate. This is controlled by a complex balancing act between networks of genes in our cells. Certain genes promote cell proliferation. These are sometimes referred to as proto-oncogenes. They were represented by a plus sign in the see-saw diagram in the previous chapter. Other genes hold the cell back, preventing too much proliferation. These genes are called tumour suppressors. They were represented by a negative sign on the same diagram.
Proto-oncogenes and tumour suppressors are not intrinsically good or bad. In healthy cells, the activities of these two classes of genes balance each other. But when regulation of these networks goes wrong, cell proliferation may become mis-regulated. If a proto-oncogene becomes over-active, it may push a cell towards a cancerous state. Conversely, if a tumour suppressor gets inactivated, it will no longer act as a brake on cell division. The outcome is the same in both cases – the cell may begin to proliferate too rapidly.
But cancer isn’t just a result of too much cell proliferation. If cells divide too quickly but are otherwise normal, they form structures called benign tumours. These may be unsightly and uncomfortable but unless they press on a vital organ and affect its activity, they are unlikely in themselves to be fatal. In full-blown cancer the cells don’t just divide too often, they are also abnormal and can start to invade other tissues.
A mole is a benign tumour. So is a little outgrowth in the inside of the large intestine, called a polyp. Neither a mole nor a polyp is dangerous in itself. The problem is that the more of these moles or polyps you have, the greater the likelihood that one of them will go the next step, and develop an abnormality that will take it further along the path towards full-blown cancer.
This implies something rather important, that has been demonstrated in a large number of studies. Cancer is not a one-off event. Cancer is a multi-step process, where each additional step takes a cell further along the road to becoming malignant. This is true even in cases where patients inherit a very strong pre-disposition to cancer. One example is pre-menopausal breast cancer, which runs in some families. Women who inherit a mutated copy of a gene called
BRCA1
are at very high risk of early and aggressive breast cancer, which is difficult to treat effectively. But even these women aren’t born with active breast cancer. It takes many years before the cancer develops, because other defects have to accumulate as well.
BRCA1
are at very high risk of early and aggressive breast cancer, which is difficult to treat effectively. But even these women aren’t born with active breast cancer. It takes many years before the cancer develops, because other defects have to accumulate as well.
So, cells accumulate defects as they move increasingly close to becoming cancerous. These defects must be transmitted from mother cell to daughter cell, because otherwise they would be lost each time a cell divided. These defects must be heritable as the cancer develops. Understandably, for a very long time, the attention of the scientific community focused on identifying mutations in the genes involved in the development of cancer. They were looking for alterations in the genetic code, the fundamental blueprint. They were particularly interested in the tumour suppressor genes as these are the genes that are usually mutated in the inherited cancer syndromes.
Humans tend to have two copies of each tumour suppressor gene, as most are carried on the autosomes. As a cell becomes increasingly cancerous, both copies of key tumour suppressor genes usually get switched off (inactivated). In many cases this may be because the gene has mutated in the cancer cells. This is known as somatic mutation – it has happened in body cells at some point during normal life. These are called somatic mutations to distinguish them from genetic mutations, the ones that are transmitted from parent to child. The mutations that inactivate the two copies of a tumour suppressor may be quite variable. In some cases there may be changes in the amino acid sequence, so that the gene can’t produce a functional protein any more. In other cases, there may be loss of the relevant part of the chromosome in the increasingly cancerous cells. In an individual patient, one copy of a specific tumour suppressor may carry a mutation that changes the amino acid sequence and the other may have suffered a micro-deletion.
It’s abundantly clear that these events do happen, and quite frequently, but often it’s been difficult to identify exactly how a tumour suppressor has mutated. In the last fifteen years, we’ve started to realise that there is another way that a tumour suppressor gene can become inactivated. The gene may be silenced epigenetically. If the DNA at the promoter becomes excessively methylated or the histones are covered in repressive modifications, the tumour suppressor will be switched off. The gene has been inactivated without changing the underlying blueprint.
The epigenetic frontier in cancer
Various labs have identified cancers where this has clearly happened. One of the first reports was in a type of kidney cancer called clear-cell renal carcinoma. A key step in the development of this kind of cancer is the inactivation of a specific tumour suppressor gene called
VHL
. In 1994, a group headed by the hugely influential Stephen Baylin from Johns Hopkins Medical Institution in Baltimore analysed the CpG island in front of the
VHL
gene. In 19 per cent of the clear-cell renal carcinoma samples that they analysed, the DNA of the island was hypermethylated. This switched off expression of this key tumour suppressor gene, and was almost certainly a major event in cancer progression in these individuals
14
.
VHL
. In 1994, a group headed by the hugely influential Stephen Baylin from Johns Hopkins Medical Institution in Baltimore analysed the CpG island in front of the
VHL
gene. In 19 per cent of the clear-cell renal carcinoma samples that they analysed, the DNA of the island was hypermethylated. This switched off expression of this key tumour suppressor gene, and was almost certainly a major event in cancer progression in these individuals
14
.
Promoter methylation was not restricted to the
VHL
tumour suppressor and renal cancer. Professor Baylin and colleagues subsequently analysed the
BRCA1
tumour suppressor gene in breast cancer. They analysed cases where there was no family history of this disease, and the cancer wasn’t caused by the mutations in
BRCA1
that we discussed a few paragraphs ago. In 13 per cent of these sporadic cases of breast cancer, the
BRCA1
CpG island was hypermethylated
15
. Broader abnormal patterns of DNA methylation in cancer were reported by Jean-Pierre Issa from the MD Anderson Cancer Center in Houston, in collaboration with Stephen Baylin. Their collaborative work showed that over 20 per cent of colon cancers had high levels of promoter DNA methylation, at many different genes simultaneously
16
.
VHL
tumour suppressor and renal cancer. Professor Baylin and colleagues subsequently analysed the
BRCA1
tumour suppressor gene in breast cancer. They analysed cases where there was no family history of this disease, and the cancer wasn’t caused by the mutations in
BRCA1
that we discussed a few paragraphs ago. In 13 per cent of these sporadic cases of breast cancer, the
BRCA1
CpG island was hypermethylated
15
. Broader abnormal patterns of DNA methylation in cancer were reported by Jean-Pierre Issa from the MD Anderson Cancer Center in Houston, in collaboration with Stephen Baylin. Their collaborative work showed that over 20 per cent of colon cancers had high levels of promoter DNA methylation, at many different genes simultaneously
16
.
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
17
. A similar relationship exists for the
PER1
tumour suppressor in a form of lung cancer called non-small cell
18
. 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.
ARHI
had low levels of acetylation in breast cancer
17
. A similar relationship exists for the
PER1
tumour suppressor in a form of lung cancer called non-small cell
18
. 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
19
. But for diseases like cancer, where we would need to treat a lot of people, it’s expensive and difficult.
19
. 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.
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.
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.
That’s because there isn’t one form of cancer. There are probably over a hundred different diseases with this name. Even if we take just one example – say breast cancer – we find that there are different types of this particular strain of cancer. Some grow in response to the female hormone called oestrogen. Some respond most strongly to a protein called epidermal growth factor. The
BRCA1
gene is inactivated or mutated in some breast cancer cases, but not in others. Some breast cancers don’t respond to any of the known cancer growth factors but to some other signals which we may not even be able to identify yet.
BRCA1
gene is inactivated or mutated in some breast cancer cases, but not in others. Some breast cancers don’t respond to any of the known cancer growth factors but to some other signals which we may not even be able to identify yet.
Because cancer is a multi-step process, two patients whose cancers appear very similar may be ill because of very different molecular processes. Their cancers may have rather different combinations of mutations, epigenetic modifications and other factors driving the growth and aggressiveness of the tumour. This means that different patients are likely to require different types and combinations of anti-cancer drugs.
Even allowing for this, however, the results from clinical trials with DNMT and HDAC inhibitors have been surprising. Neither of them has yet been shown to work well in solid tumours such as cancers of the breast, colon or prostate. Instead, they are most effective against cancers that have developed from cells that give rise to the circulating white blood cells that are part of our defences against pathogens. These are referred to as haematological tumours. It’s not clear why the current epigenetic drugs don’t seem to be effective against solid tumours. It might be that there are different molecular mechanisms at work in these, compared with haematological cancers. Alternatively, it could be that the drugs can’t get into solid tumours at high enough concentrations to affect most of the cancer cells.
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