Grow your enemy
If you had cancer, would you want to make clones of your tumour?
The first doctor I saw told me I had six months to live,” says Antonia Crawford. She was diagnosed with advanced pancreatic cancer in August 2013, at the age of 43. She went on to have the standard treatments but, aware that they might not be the most effective against her particular cancer, Crawford also did something quite extraordinary: she had bits of her tumour implanted into a group of mice. Once the tumours had grown in them, the mice were given a range of different treatments, in an effort to find the drug combination that would work best for her. “As a patient, I just didn’t have the time, nor could my body have gone through trying all these different drugs on myself,” Crawford says.
It’s too early to say whether this particular method improves individuals’ chances of survival. But there is a lot of interest in the idea. Many groups are working on the somewhat grotesque challenge of growing three-dimensional copies of people’s tumours outside the body – essentially, cloning cancers. Simply put, the idea is that if you want to know your enemy, you need to grow your enemy.
While cancer cells have long been grown outside the body, it isn’t as easy as you might think. Some, such as the famous HeLa strain of cells long used in research, thrive outside the body, but most cancer cells die if they are stuck in a dish. And even when they do survive, there is a big difference between a bunch of cancer cells growing in some fluid in a dish and a tumour growing in someone’s body. Solid tumours are a bit like organs: they have a mix of cell types growing in a three-dimensional structure and fed by a dedicated blood supply. “How cells behave in 2D in a plastic tissue culture flask is just not that relevant to what happens in the body,” says Frances Balkwill of Barts Cancer Institute in London. Balkwill’s team and others around the world are trying to grow realistic tumours outside the body using tissue engineering, but this approach is still at an early stage. The tried and tested way of growing tumours in 3D is to implant bits in mice with an immune system altered so as not to attack human cells. Such xenografts have been used for drug testing since the 1980s.
Now Champions Oncology – the company that Crawford turned to – is selling this service directly to individuals with cancer. “Cancer is a unique disease, and it is very difficult to work out why some drugs will work for one patient but won’t work for another; we need a more rational way to figure out what patients should and shouldn’t try,” says Ronnie Morris, the company’s president.
This everyone agrees on. Cancers are already classified into hundreds of different types depending on which tissue they originate in and what they look like under a microscope. But really there are many millions of kinds. Cancers typically have hundreds of mutations, along with even more epigenetic changes. Every tumour is unique – and constantly changing and evolving.
Getting personal
So the more closely treatment can be tailored to a person’s particular cancer, the more effective it is likely to be. And personalised treatments are starting to become a reality. People whose tumours produce too much of a protein called Her2, for instance, are given specific drugs that work against this form of cancer. Genetic tests are also increasingly used to identify mutations known to affect how cancers behave. But while the field is advancing extremely rapidly, we are still far from the point where we can predict the best possible drug combination from genetic tests alone.
Indeed, there are reasons to doubt we ever will reach this point. The cells tested might not be representative of the whole tumour, for instance. What’s more, the non-malignant cells in a tumour can have a big effect on the way it evolves and responds to treatment.
This, Morris says, is where Champions can help. “Building a very close replica of their tumour that’s alive and continues to grow in
a host environment gives patients the ability to simultaneously test four or five drugs or combinations, so that they can see which is the most effective.”
In late 2013, Crawford underwent chemotherapy and radiotherapy that shrank her tumour enough for surgeons to try and remove it from her pancreas. Her brother paid for a piece of the tumour to be cut up and implanted on the backs of several mice. After the tumours had grown somewhat, they were used to “infect” even more mice. Around five months on, Champions had created a small army of what cancer researchers call mouse “avatars”. These were given combinations of drugs that genetic testing suggested might work to see which, if any, could shrink
the tumours.
Champions says that the animals’ suffering is minimal because the tumours grow just under the skin and don’t invade organs. This was an important consideration for Crawford. “I know that animal testing is a sensitive subject, but when you find yourself in a position where you’re reliant on it, you realise that it’s quite vital,” she says. “The only other option for me was to go through it all myself; I would be suffering pain, and my time might run out.”
The process isn’t cheap. Just creating the mouse avatars costs around £1500, and it doesn’t always work on the first attempt; the success rate is around 70 per cent, Morris says. Then it’s a further £2500 for each drug tested. Given that most patients opt to test four or five drugs, that’s £11,500 to £14,000. Is it worth it?
Preliminary studies by Champions suggest that the mice’s response to the cancer drugs does reflect what happens in the patient fairly well. In one study, 65 mouse avatars were given the same second- or third-line drugs as the people whose tumours they had received. According to a poster presentation given at a European Society of Medical Oncology meeting last year, there was an 87 per cent correlation between positive responses in mice and humans. “To put that in context, when a patient takes a second- or third-line drug, the chance of success is usually 10 to 15 per cent,” says Morris.
Mouse avatars
The numbers may sound impressive, but this was a small study and the mouse avatars were not actually used to choose treatments. Other researchers would like to see more extensive testing of the approach before more people are persuaded to part with their cash.
“Using avatar mice to try to predict patients’ responses to treatment is an intriguing new approach to personalising medicine, but it’s still at an experimental stage,” says Emma Smith of Cancer Research UK. “It may be of benefit to some cancer patients in the future, but we’ll need more research to determine if and for whom it might be helpful. In the meantime, it’s vital that patients speak to their oncologist before deciding to pursue any experimental testing method.”
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