Targeting cancer's Achilles' heel

21 March 2010
Posted by Chris Smith.

Cancer is a disease caused by gene faults - both inherited from our parents and picked up during our lifetime as our DNA gets damaged. And increasingly, researchers are working out how to use these faults to our advantage to fight the disease.

This week, research from Professor Alan Ashworth and his team at The Institute of Cancer Research, funded by Cancer Research UK, has revealed another Achilles' heel in cancer cells that we can try and target. They've just published their results in the journal Cancer Cell.

Dying Achilles at Achilleion, Corfu. Sculptor: Ernst Herter, 1884.The new research is based on the concept of synthetic lethality. In our cells, we have multiple ways of doing the same thing, which help to protect us if something goes wrong. It's a bit like a pair of trousers with a belt and braces holding them up - so if the belt breaks, then the braces still work to preserve your dignity.

But cancer cells have a lot of faults, and in many cases they're just relying on one mechanism to do something - to use our analogy, the belt is broken, and they're relying solely on their braces. So if we can figure out what they're dependent on, and target it with drugs - to snip the braces - then that might be a good way to treat cancer.

Professor Ashworth and his team looked at cancer cells that had faults in specific genes involved in repairing damaged DNA - genes called MLH1 and MSH2.  Faults in these genes have been found in a number of different cancers, including bowel cancer.

Faults in either of these genes mean that cells tend to accumulate DNA damage, helping to turn them cancerous. But other pathways in the cell - the metaphorical braces - can still compensate for the lack of MLH1 or MSH2, so the cancer grows and spreads.

Here's where it gets clever. The researchers realised that molecules called DNA polymerases - which help to copy DNA when cells divide - were also repairing DNA, and compensating for the lack of MLH1 and MSH2.

The researchers used a technique called RNAi to knock out certain DNA polymerases in cancer cells lacking either MLH1 or MSH2. And they found that knocking out a polymerase called POLB could kill cells lacking MSH2, while targeting another polymerase called POLG could kill cells without MLH1.

We already know that this kind of approach works to treat cancer - we're starting to see very promising results from early clinical trials of new cancer drugs called PARP inhibitors, which work along the same principles, but targeting different pathways in the cell.

At the moment, the technique the researchers used to block POLB or POLG isn't easily transferable to patients (as we'll hear in my second news story). So scientists now need to find small chemicals that could be developed into drugs that would have the same effect. Although that's still some way away, this is a promising approach.

This research also highlights that we need to focus on the specific faulty pathways in cancer cells, rather than just the overall type of cancer. For example, faults in MLH1 and MSH2 are found in a subset of several different types of cancer, so they might all respond to polymerase-blocking drugs. We're starting to move away from thinking about treating "bowel cancer", or "breast cancer" etc., and towards treating "MLH1-deficient cancer cells", targeting the genetic faults that are specific to an individual patient.

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