Another Brick in the Wall: Turning cancer’s strengths against it

A mutation that allows cells to grow out of control could also provide a new way to target and destroy cancer cells. This potential Achilles’ heel comes from a mutation in a gene called PTEN, which is found in a wide range of cancers.

PTEN is one of many tumour suppressor genes that we have to prevent our cells from growing out of control. If the PTEN gene stops working because of a mutation, it can cause tumours to develop – indeed many tumours have a mutated form of PTEN. However when a door closes, a window opens: the PTEN mutation helps the tumour to grow, but it could also mark it out as a target.

Researchers from the Institute of Cancer Research, London, found that switching off another gene known as NLK killed tumour cells that had the PTEN mutation. This makes NLK a good target for drug developers to create a new cancer treatment.

The difficult thing about cancer is that it is made of us – it is our own cells that have mutated and grow wildly out of control. That means it is unlikely there will ever be a quick fix. Antibiotics work efficiently because bacteria are so different to us that we can develop drugs that target their weaknesses yet barely affect our own cells. But how do you kill something that is the same as you? Current treatments for cancer cause a lot of side-effects in patients because as they try to kill the cancer they also do damage everything else in the body. This is why finding ways to target cancer specifically is so important.

There are several proteins which we cannot live without, and our cells die if the genes responsible for producing those proteins are mutated or switched off. Targeting these proteins and genes are rarely going to be useful for treatments, as they will kill the patient about as quickly as they kill the cancer. So Alan Ashworth and colleagues set out to find proteins that are not essential in healthy cells, but cells with the PTEN mutation cannot live without. This would pave the way for designing drugs that target the tumour and leave healthy cells alone.

The researchers took samples of tumour cells with and without the mutation, and switched off genes for important proteins that are used for regulating lots of processes in the cell. To do this they used small molecules of RNA (DNA’s less famous cousin) which interfere with the processes of specific genes. This is why these molecules are known as small interfering RNA (or siRNA). They block the chain of events that allow a gene to produce a protein, effectively switching it off. By switching off 779 genes individually, they could look for ones where cells with the PTEN mutation died and cells without the mutation survived.

This is how the researchers discovered the powerful effect of switching off the NLK gene. They are not certain how this works but it appears to protect a protein called FOXO1 that can act as a backup tumour suppressor and cause the cancer cell to die. When PTEN is mutated, the FOXO1 protein becomes vulnerable to a process called phosphorylation, which means it is ejected from the cell nucleus and destroyed. NLK is one of the proteins that phosphorylates FOXO1 and so by switching off the NLK gene, FOXO1 is able to do its job.

The phosphate group, shown at the top, consists of one phosphorus atom (in orange) and three oxygen atoms (in red). This can be added to certain amino acids to control the behaviour of the whole protein

Phosphorylation is the process of adding a phosphate group, shown at the top, to certain amino acids to control the behaviour of the whole protein. This group consists of one phosphorus atom (in orange) and three oxygen atoms (in red) and has a strong negative charge.

This is just the start of a long journey from the lab to (potentially) the hospital. The researchers have shown that targeting NLK is more likely to kill mutated cells than normal cells, but that does not mean it is safe. NLK still has a role to play in healthy cells and preventing it from working is likely to have side-effects, but it could be worthwhile if this approach can kill tumours. The next stage is to develop a drug to stop the NLK protein from working, so that it can be tested further in cells and in living organisms.

Promising leads against cancer appear often, yet very few ever make it as treatments. One big hurdle is making it through clinical trials; the new drug has to be better than currently available treatments. Targeting NLK would only work against cancers with the PTEN mutation, but now we can use the mutation as a marker to find out which patients that applies to. We are now in the age of personalised medicine, where we can have 100 different treatments for 100 different people with 100 different cancers. Gradually, we are finding ways to attack cancer in whichever form it appears and build up our range of treatments. The weaknesses that we find are not going to cure all cancers, but each one provides another brick in the wall.

This article was originally written for the Access to Understanding competition run by Europe PubMed Central


…and this little piggy corrected genetic mutations

Scientists have come a step closer to being able to correct mistakes in our DNA, thanks to a new method for rewriting mutations in stem cells. This could be used to treat genetic diseases for which there are no treatments available.

The researchers made use of piggyBac, a ‘jumping gene‘ originally found in moths. These ‘jumping genes’, as their name suggests, move from place to place along the DNA and can be used to carry other genes with them. Acting as a genetic cut-and-paste, they can neatly insert a corrected gene with remarkable precision. “Our systems leave behind no trace of the genetic manipulation, save for the gene correction,” says Professor Allan Bradley of the Wellcome Trust Sanger Institute.

In the case described in Nature the team focused on a genetic liver disease.

Severe deficiency in the protein alpha 1-antitrypsin is caused by a mutation, which is found in 1 in 2000 North Europeans. This protein is produced in the liver, but is responsible for protecting the lungs. The mutation causes the protein to accumulate in the liver, leading to cirrhosis, and deplete in the lungs, causing emphysema.

The scientists converted samples of patients’ skin cells into stem cells and corrected the mutation, using piggyBac. These stem cells were then converted into liver cells, in test tubes and in mice, which were able to produce the correct form of the protein.

Despite advances in the technology, producing stem cells in this fashion introduces new mutations into the DNA. While most of these mutations are likely to be harmless, there can be potentially fatal side-effects. This risk will need to be minimized before the technique is brought forward to treating patients.

Currently the only cure for alpha 1-antitrypsin deficiency is a liver transplant, but with transplant waiting lists longer than ever, this new development can bring hope to thousands of sufferers.