All treatments for cancer should be designed to prevent tumours evolving resistance, because drug-resistant tumours are what kill most people, says Paul Workman, head of the Institute of Cancer Research in the UK.
To make this happen, the ICR is setting up a £78 million Centre for Cancer Drug Discovery in London that will bring together researchers from different disciplines to focus on creating anti-evolution treatments.
“We are hugely excited about it,” Workman told a press briefing at the Science Media Centre. “The biggest challenge in cancer is drug resistance.”
When someone with cancer is given a drug, it may be very effective at first, killing most of the cells in the tumour. But if just a few cells out of the billions in a tumour have a mutation that makes them resistant to that drug, they will survive and keep growing.
This is natural selection – exactly the same process that drives the evolution of plants, animals, bacteria and viruses. “Cancers evolve very rapidly over a short space of time to become resistant, leading to the vast majority of cancer deaths,” says Workman.
Thanks to new technologies such as single-cell genome sequencing, we can now study this process in action. But cancer researchers and doctors have not yet put this understanding at the heart of all they do.
“We need a culture shift in how we develop drugs,” says Olivia Rossanese, who will be head of biology in the new centre.
One approach to prevent resistance evolving could be to combine drugs with different killing mechanisms. While some cancer cells may be able to resist one or two drugs, it’s rare for any cells to have mutations that will let them survive three at once.
Triple drug therapy has been the key to halting evolution in HIV, Workman points out. The virus can evolve resistance to one drug but very seldom to three.
However, for this to work, people will usually need to get the combination from the start. Once a cancer is resistant to one drug, giving the other two won’t prevent resistance.
But the trouble is that drugs are usually developed and tested for safety individually, and may be more dangerous if combined. “The existing way of getting drugs approved does not lend itself to doing this,” says Workman.
Another approach is to limit cells’ ability to evolve by stopping them mutating. For instance, mutations in cancer cells are often induced by enzymes called APOBEC proteins. These proteins’ normal function is to generate the diversity our immune system needs to respond to new diseases, but cancers hijack them and use them to evolve resistance.
Researchers at the ICR are already working on drugs that block specific APOBEC proteins. If given in conjunction with existing treatments, they may slow the evolution of resistance.
A third approach is known as evolutionary herding. The idea here is not to stop evolution but to force it to take a certain direction, for instance by using a drug that makes it more vulnerable to other treatments, rather than more resistant. These other treatments can then be deployed later on.
“The aim is to direct cancer cells towards an evolutionary dead end,” says Andrea Sottoriva, another researcher who will work at the centre.
Finally, another idea is to monitor how cancers are evolving and keep adapting treatments to maintain their effectiveness. This could be done with “liquid biopsies” – blood tests that detect substances shed by tumours.
The researchers hope that having a whole centre dedicated to this anti-evolution approach will help bring about a major shift in cancer research, so that treatments focus on preventing resistance in the first place, rather than becoming ineffective one after the other. “We need to stop play catch-up,” says Rossanese.
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