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Let's beat cancer sooner

Some capsules of drugsDoctors use many different drugs to treat cancer, and researchers around the world are working hard to develop new ones. But what about designing drugs that actually prevent the disease?

One of our promising young researchers is aiming to do just that. We’ve just awarded a prestigious fellowship to Dr Geoff Wells at the London School of Pharmacy so he can carry out research into drugs that could protect cells from turning cancerous – an approach known as chemoprevention.

Such drugs could be used to prevent cancer in people who are known to have an increased risk of developing cancer – such as someone who has inherited a faulty gene from their parents that raises their risk of cancer.

So developing chemopreventative drugs could save lives. And Dr Wells has formulated an exciting plan for going about it.

Damaged DNA
Our cells contain DNA, the genetic material we inherit from our parents.  The majority of cancers are the result of damaged DNA that accumulates over a person’s lifetime, which can occur through exposure to certain chemicals – for example, the harmful by-products from reactions that occur naturally in our cells to generate energy, or the 69 carcinogens found in cigarette smoke.

If all this sounds a bit scary, the good news is that our cells have systems in place that can provide protection from these damaging chemicals after exposure to them.

The ‘master switch’ for several of these systems is a molecule called Nrf2, which can activate a number of anti-cancer genes, increasing the cancer-fighting ability of the cell.

Levels of Nrf2 in a cell are controlled by a second molecule called Keap1.This molecule is capable of binding to it Nrf2 and ‘tagging’ it for destruction by the cell’s garbage disposal system.

This provides the cell with a nice, neat control mechanism for turning its protection systems off when they’re not needed.

But for people at very high risk of cancer, it might be useful to keep these systems turned on all the time.

So Dr Wells thinks that blocking Keap1 from binding to Nrf2 – by targeting it with drugs – could keep levels of Nrf2 permanently high and so help protect cells from cancer-causing damage.

Keap-ing it quiet
Some naturally-occurring chemicals that are found in low levels in certain foods or plant extracts can stop Keap1 from sticking to Nrf2. And Cancer Research UK is funding researchers in Leicester who are investigating the cancer-prevention potential of some of these.

But Dr Wells is coming from a different angle to design a cancer prevention drug.

Thanks to a sophisticated technique called X-ray crystallography, scientists have worked out the exact three dimensional shape of the region in Keap1 that binds with Nrf2. So Dr Wells is looking for molecules that fit into this unique shape and block the two from binding.

Tweaking and testing
He plans to do this using a number of different approaches – including using computers to virtually ‘test’ thousands of molecules, and designing new ones himself.

Dr Wells will then buy or manufacture molecules that look like they’re the best fit for Keap1.

The next step is lab tests to see which of these is most effective – such as finding out how well they block Keap1 and Nrf2 binding, and how they affect the activity of Nrf2 in cells.

The best molecules from this first round of testing will get tweaked to make them even better for a second round of tests, and so on…

And once he has narrowed down his ‘lead molecules’, the plan is to develop them further and find out if they are safe to give to people.

Ultimately, Dr Wells hopes to test any potential new drugs in large clinical trials to find out whether they are safe and – crucially – whether they can prevent cancer.

Precision approach
Many chemoprevention drugs that are currently in development are based on ‘active’ naturally-occurring extracts from food or plants. But these are often a mixture of different chemicals – which means that their effects can be unpredictable.

The advantage of Dr Wells’ new approach of designing very specific drugs is that they are less likely to have unwanted side effects and will therefore be more likely to be safe to give people for long periods of time.

Although the intention is to target high-risk individuals with these drugs, if they’re successful, could we all one day be popping our daily pills to reduce our risk of developing cancer, much like people do with statins and heart disease?

But no drug is entirely side-effect free. Using drugs to prevent cancer would probably mean a trade-off between serious side-effects of expensive cancer treatment, against higher rates of minor side-effects, and the associated cost of giving drugs to many more people. Is this a good idea?  What do you think?

Alison Ross, Senior Science Information Officer

Comments

COLIN December 9, 2008

This not only sounds interesting work but I would love to be involved in it. Do I think that is practical no. Reason? Due to age – over the age of official retirement. My qualifications?
MSc ( taught ) with the Open University following BSc Honours specialising in Chemistry with the Open University. Currently studying a short course with the Open University on “Understanding Cancer”. Would I require a salary? No. Why? because I am pursuing several leisure activities at the moment and I think it would be rather more appropriate to spend some time on assisting research rather than placing money in collector’s boxes.
If Dr Wells has any thoughts or suggestions I would welcome them.

Helen December 8, 2008

This is really interesting work that offers exciting promise for the future. Prevention is definitely better than cure – but for population-wide chemoprevention to take off, the side effects would have to be pretty minimal.