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A model of the histone deacetylase (HDAC) enzyme, the target of a new class of drugs

By Dr Lindsey Goff

(Queen Mary University of London, Institute of Cancer)

August 2006
Langs vertaald Benno Arentsen

Cancer is not just one disease with one cause. There are billions of cells in our body each home to a multitude of tightly-controlled biochemical activities. So there are numerous points where control can break down and cause cancer. In each case the key feature is unbridled growth with no respect for surroundings or neighbouring cells, a roguish behaviour that vandalises the host and, if left unchecked, may have fatal consequences. The more we understand about how normal cells can go wrong, the more potential therapeutic targets we can uncover for investigation. For example, the discovery of the faulty Her2 gene that spurs on tumour growth in 25% of breast cancer patients has led directly to an anti-Her2 therapy, prolonging the lives of many. All this is thanks to genome research. And the hunt for therapies is now exploring our epigenome, the orchestrator of genome activity, broadening the horizon for cancer therapeutics.

The epigenome controls which stretches of DNA are active. Our genome wraps around cellular capstans, histones, which are tagged by enzymes with molecules such as acetyl and methyl. The tagging and wrapping both determine which genes (stretches of DNA) are switched on and which are not. When genes are managed properly cells are kept in order, but when they act inappropriately, they cause cellular anti-social behaviour. Changes in the behaviour of two epigenetic enzymes, Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) seem to play a role in many cancers by switching on the wrong set of genes. Readjusting the HDAC:HAT balance has proved a useful anti-cancer strategy and led to a family of drugs called HDAC inhibitors (HDACI), which are currently leading the race to the bedside.

HDACIs can shrink blood cancers like leukaemia and lymphoma and many solid tumours such as prostate, colo-rectal and kidney. One HDACI, SAHA, has already reached Phase III clinical trials. This means it has reached human patients but will need further testing before becoming a standard cancer treatment. All cells, normal and cancerous, use HDACs, but luckily cancer cells are more likely to be killed by their inhibitors than normal cells. Some cancers respond better to HDACIs so the drugs have been targeted at certain tumour types.

Cancer cells are masters of disguise. Although they are obviously unwanted by their host they usually go unnoticed because of their disorderly but ingenious array of gene expression. Understanding the epigenome will yield new and exciting ways to reveal cancers and help our immune system to fight back. HDACI-research shows that these drugs can switch on immune genes (called MHC) which help the body to recognise foreign or unwanted invaders. Now the focus will be to hone drug-specificity and identify patients with the most responsive tumours. Many anti-cancer drugs are used in combinations for optimal results so maybe HDACIs will realise their greatest potential in this way. In any case the arsenal of anti-cancer therapies continues to grow.

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