Virus in Disguise

Ovarian cancer affects over 6,600 women in the UK, and 190,000 worldwide, every year. What’s more, treating it successfully can be difficult. Women are often diagnosed after the cancer has started to spread, and ovarian tumours can be notoriously ‘drug resistant’ – chemotherapy works for a short time but then the cancer starts growing again.

So a new approach is urgently needed.

One strategy under investigation by many of the world’s cancer researchers – including teams funded by Cancer Research UK – is to develop genetically engineered viruses that only multiply inside cancer cells and kill them. Much of this research is based around tweaking a harmless cold virus called adenovirus, turning it into a cancer killer.

Disappointingly, most of the clinical trials of these viruses so far have had poor results. But there’s hope on the horizon. A new approach from Professor Len Seymour and his team, funded by Cancer Research UK, could revive the flagging hopes for virus therapy for ovarian cancer.

Trial troubles
The lack of success for viruses in clinical trials for ovarian cancer comes down to a few reasons. Firstly, the fluid in the abdomen that surrounds the ovaries is packed with antibodies that can neutralise the virus. And ovarian cancer cells don’t have many of the receptor molecules that recognise the virus and take it up into the cells. Both of these things limit the number of viruses that actually make it into cancer cells to carry out their deadly work.

The trials have also run into problems with side effects. Doctors have found that patients treated with the virus suffer from a rather unpleasant problem called ‘adhesions’. This means that parts of their internal organs start to stick together – probably as a result of inflammation due to the presence of the virus – which isn’t good news.

First, cloak your virus
Professor Seymour and his team are using a two-step approach to solving these problems. The first step is to ‘cloak’ the virus, so it isn’t recognised by the body.

The researchers do this by coating the virus particles with long chains of a polymer called HPMA, which has previously been used to deliver drugs safely in clinical trials.

The cloaked viruses are effectively disguised from the immune system, and so are much less likely to be recognised and neutralised. But this also means that they can’t get into cancer cells, as they’re no longer recognised by the cells’ virus receptors.

Then give it a disguise
So here’s the second step. To get round the problem of the virus’ new-found invisibility cloak, the team give it a clever disguise – a bit like a molecular ‘false moustache’.

Many cancer cells, including those from ovarian cancers, have high levels of a receptor for EGF, a chemical growth signal, on their surface. In fact, around two-thirds of ovarian cancers have extra EGF receptors.

So here’s the really clever bit – the researchers attach EGF molecules to the virus, allowing it to stick to cancer cells via their EGF receptors. The cancer cells then take up the virus, as they have been tricked into thinking that it is EGF. Once inside a cancer cell, the virus then sheds its disguise, multiplies rapidly, and kills it.

Lab tests
The scientists tested their cloaked, EGF-targeted adenovirus in ovarian cancer cells grown in the lab. They found that the virus was smuggled into the cells, and killed them.

Then the team tested it in mice carrying ovarian tumours. They found that mice given the cloaked, targeted virus survived nearly twice as long as those given a salt solution as a control, and also lived longer than mice treated with the cloaked, untargeted virus.

The scientists also found that mice given doses of uncloaked virus had similar side effects to those seen in patients on previous clinical trials involving viruses – including adhesions. But when the team tested the cloaked virus, no adhesions were seen. This bodes well for the safety of the treatment in future clinical studies.

In these experiments, the team used normal, non-engineered adenoviruses, as experiments have shown that they still have some cancer-killing effects. But other researchers have developed genetically engineered adenoviruses that are more powerful at killing cancer cells and could be tested in future experiments.

Not just ovarian cancer

Because EGFR is found on many cancers, the technique could be applicable to other cancer types. Prof Seymour’s team are also working on using molecules other than EGF to target the virus to cancer cells – for example, they’ve just published a paper showing that they could also exploit another growth factor involved in cancer – FGF.

At the moment, this work is just a ‘proof-of-principle’, and a lot more research is needed, such as testing engineered viruses and improving the effectiveness of virus delivery. But it’s a good start.

It was funded by Cancer Research UK, Oxfordshire Health Services Research Council, Wellbeing of Women, and Macmillan Cancer Relief.