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.
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.
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.
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.
Even within haematological tumours, there are differences between the DNMT and HDAC inhibitor drugs. Both DNMT inhibitors have been licensed for use in a condition called myelodysplastic syndrome[186][187]. This is a disorder of the bone marrow.
Both HDAC inhibitors have been licensed for a different kind of haematological tumour, called cutaneous T cell lymphoma[188]. In this disease, the skin becomes infiltrated with proliferating immunological cells called T cells, creating visible plaques and large lesions.
Not every patient with myelodysplastic syndrome or cutaneous T cell lymphoma gains a clinical benefit from taking these drugs. Even amongst the patients who do respond, none of these drugs really seem to cure the condition. If the patients stop taking the drugs, the cancer regains its hold. The DNMT1 inhibitors and the HDAC inhibitors seem to rein in the cancer cell growth, retarding and repressing it. They control rather than cure.
However, this often represents a significant improvement for the patients, bringing prolonged life expectancy and/or improved quality of life. For example, many patients with cutaneous T cell lymphoma suffer significant pain and distress because their lesions are constantly and excruciatingly itchy. The HDAC inhibitors are often very effective at calming this aspect of the cancer, even in patients whose survival times aren’t improved by these drugs.
Generally speaking, it’s often very difficult to know which patients will benefit from a specific new anti-cancer drug. This is one of the biggest problems facing the companies working on new epigenetic therapies for the treatment of cancer. Even now, several years after the first licences were granted by the FDA for 5-azacytidine and SAHA, we still don’t know why they work so much better in myelodysplastic syndrome and cutaneous T cell lymphoma than in other cancers. It just so happened that in the early clinical trials in humans, patients who had these conditions responded more strongly than patients with other types of cancers. Once the clinicians running the trials noticed this, later trials were designed that focused around these patient groups.
This may not sound like a major difficulty. It might seem straightforward for companies to develop drugs and then test them in all sorts of cancers and with all sorts of combinations of other cancer drugs, to work out how to use them best.
The problem with this is the expense. If we check out the website of the National Cancer Institute, we can look for the number of trials that are in progress for a specific drug. In February 2011, there were 88 trials to test SAHA[189]. It’s difficult to get definitive costs for how much clinical trials cost, but based on data from 2007, a value of $20,000 per patient is probably a conservative estimate[190]. Assuming each trial contains twenty patients, this would mean that the costs just for testing SAHA in the trials at the National Cancer Institute are over $35,000,000. And this is almost certainly an under-estimate of the overall cost.
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.
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http://www.masshightech.com/stories/2008/04/21/story1-Epigenetics-is-the-word-on-bio-investors-lips.html