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

Advertisements

Red Alert: How red hair can cause skin cancer without sun exposure

I’m not usually that interested in research completely based on mouse studies, but any paper that starts with ‘People with pale skin, red hair, freckles and an inability to tan…‘ is always going to get my attention.

People like me, with the ‘red hair/fair skin’ phenotype, are pretty bad at dealing with the sun. Not only do we get sunburnt much more easily, but we have the highest risk of developing melanoma, the deadliest form of skin cancer. It is (hopefully) very well known that exposure to UV light increases the risk of melanoma. However, unlike other other skin cancers, melanoma also appears to develop independently of UV light, although this has been poorly studied to date.

The sun can be your worst enemy when you’re ginger. (Photo credit: coltera)

In a letter published in Nature this week, researchers wanted to see if hair-colour pigments affect this UV-independent pathway for melanoma. To do this, they engineered mice to mimic human complexions by mutating a gene known as MC1R. This is responsible for producing the pigment eumelanin which is dark coloured and results in dark hair. Most people with red hair have an inactive form of MC1R, which instead leads to the red-coloured pheomelanin being produced.

The researchers compared mice with black hair (active MC1R), red hair (inactivated MC1R) and albinism (produces neither pigment). In addition, all the mice had a specific mutation that causes benign moles, but leaves them predisposed to developing melanoma. The mice were kept away from sources of UV light and their health was charted over time.

The differences are startling. In under a year 50% of the red-haired mice had died compared to only 20% of the black-haired or albino mice. This, and further tests, seem to suggest that producing pheomelanin is actually harmful, increasing the rate of melanoma when there is no UV light.

Pheomelanin is responsible for the colour of red hair, but could also cause cancer

It was also apparent that the DNA of the red-haired mice had suffered twice as much oxidative damage as the albino mice. It is known that UV light causes oxidative DNA damage and that this increases the chances of mutations occurring. In previous studies looking at UV radiation, it was thought that eumelanin protects against this damage. However, the mice in this study show that pheomelanin is actually harmful and eumelanin has little effect under these conditions. It’s still not clear how this damage was created in the absence of UV light or why production of pheomelanin made it worse.

The authors of the paper make it very clear that UV radiation is still an important factor in the development of skin cancer, but suggest that this UV-independent pathway should be considered in the future for strategies to prevent melanoma, especially for gingers.

Redheads have long understood that we lack the natural sun protection that others enjoy, but it is still quite a shock to think that our distinctive colouring is actively causing us damage. However, this study was done under very artificial conditions, and the rates that the researchers saw are far higher than we can plainly observe. After all, we don’t see half of redheads dying every year. But whatever your hair colour, melanoma is still very deadly – one American dies from melanoma every hour. So make sure you don’t forget your sunscreen.

Magnetic trigger for cancer death

A team of researchers from Seoul have developed a magnetically-controlled nanoparticle that can kill cancer cells.

One of the key challenges in the fight against cancer is that potential treatments can often be worse than the disease. These treatments are so destructive that it takes a lot of effort to find one that will kill the cancer before it kills the patient. This means that treatments need to be as selective and controllable as possible.

The nanoparticle can be controlled by simply turning a magnetic field on and off. This means that its effects can be aimed at a specific area (if you have a focused magnetic field) and for a specific length of time. This level of targeting would reduce the severity of side-effects, allowing patients to receive stronger doses.

The zinc-doped iron oxide nanoparticle is attached to an antibody which binds tightly to death receptor 4, DR4. There are many copies of DR4 on the surface of the cancer cell and the nanoparticles can bind to them all, without any effect. When a magnetic field is applied, the nanoparticles move towards one another across the cell surface. This causes the DR4s to come together to form a complex. This is known as death-inducing signalling complex and it starts the chain reaction of events leading to apoptosis (programmed cell death).

Antibodies bind very specifically to their target protein, making them very useful in medicine

This mechanism is actually a mimic of the one used by the TNF-related apoptosis inducing ligand (TRAIL). TRAIL has been investigated as a cancer treatment, however it degrades easily, a problem that is unlikely to affect the nanoparticles.

The paper, published in Nature Materials, looks at the effect on cancer cells in vitro and the effects on zebrafish. This research is still very much in the early stages and it will be quite some time before its effects on cancer in humans can be tested. However, it is a fine example of the novel ways that scientists are trying to fight cancer. It is the trickiest disease there is, and it will take a lot of ingenuity to tackle it.