Image: Professor Trevor Graham took his QMUL lab to see Charles Darwin's former home in Kent.
When Charles Darwin’s theory of evolution was first published, in 1859, you can be confident he was not aware he was also describing many of the rules that govern cancer.
Yet evolution is at the heart of cancer - its laws explain both how cancer develops and how it grows to resist the treatments we throw at it.
Finding simple rules to explain something incredibly complex is a major driver for Professor Trevor Graham, who is joining The Institute of Cancer Research, London, as the new Director of our Centre for Evolution and Cancer.
In his current role at the Barts Cancer Institute, Queen Mary University of London, he’s brought together mathematicians, evolutionary biologists, zoologists, physicists, cell biologists, clinicians - to make gains against cancer. This multidisciplinary approach chimes well with the existing strategy of the Centre for Evolution and Cancer, and the Centre for Cancer Drug Discovery where it is housed.
He is passionate about harnessing the principles of evolution to predict when cancer will develop, better tailor treatments to individual patients, and to overcome one of the biggest challenges facing cancer research today - drug resistance.
Reconstructing cancer’s mutational past
Advances in computational science mean we can now use artificial intelligence (AI) to recreate the evolutionary history of a tumour and map its future.
Professor Graham explains: “My team create computational tools that reconstruct cancer’s mutational past and allow us to make predictions about the future. We call this an ‘evolutionary trajectory’.”
According to Professor Graham, we can now use genomic data to make very accurate predictions about the likelihood of a cell's journey from precancerous to cancerous, and from treatment-sensitive to treatment-resistant.
Predicting cancer’s development
Professor Graham, who originally trained as a mathematician, before doing an interdisciplinary PhD in Mathematical Biology, is particularly interested in gastrointestinal (GI) cancers, including those that stem from chronic GI diseases including ulcerative colitis, and Barrett’s oesophagus.
“One area I’m interested in is inflammatory bowel disease, including Crohn's and ulcerative colitis, which unfortunately raise the risk of bowel cancer. We want to be able to spot those patients who will develop cancer as early as possible. A big issue is working out which cells have maybe taken the first step towards becoming cancerous, and whether they're actually going to run the rest of the race and become a cancer.
“Together with Professor Ailsa Hart and her brilliant colleagues at St Mark’s Hospital, the UK’s specialist bowel hospital, we’re working on mathematical models that input mutational patterns to predict the risk that a cancer will evolve. With just a small biopsy taken during a routine colonoscopy, we can use genomics to spot the cells that have taken their first steps toward becoming cancerous. We can predict accurately whether someone will go on to develop cancer maybe five years in advance, and take action.”
In this case, action is usually the removal of part of the bowel. Mathematical models can determine in which cases this major surgery is necessary, and for whom it can be avoided or delayed.
“It’s all about the patient. With our tools, doctors will have important new information to help patients make a more informed choice about their treatment.”
Our Centre for Evolution and Cancer aims to help us understand how cancer evolves and adapts, and to find more effective ways to treat it.
Find out more
Professor Graham is also interested in finding clever ways to manipulate cancer evolution and improve the sensitivity of tumours to new treatments.
“Cells from different areas of a single tumour have different alterations in their genetic code, and it can be almost impossible to kill all of the cells with a single drug. A few unique cells are often left after treatment. They’ll grow back and resist treatment. It’s evolution right in front of our eyes.”
Instead of trying to wipe cells out completely, Professor Graham is exploring a new technique, where treatments are added and removed depending on the population of different cancer cell types.
“There’s a complex and dynamic interplay between different populations of cancer cells within tumours and I’m interested in how we can manipulate this competition to our advantage.”
According to Professor Graham, the idea that different cell populations within tumours can be ‘played against each other’ is gaining traction. The idea, which involves titrating drug doses depending on the number of sensitive cells in the tumour, was first proposed by one of his inspirations, Professor Robert Gatenby, from the Moffitt Cancer Centre in Tampa, Florida.
'No such thing as a free lunch'
“Even for cancer cells, there’s no such thing as a free lunch. Cells that have evolved resistance to treatment will usually also have a disadvantage. For example, one idea is that resistant cells often develop pumps on their surface that allow them to get rid of the drug, but this also means they use extra energy.
“The idea is that when the drug is present, resistant cells have an advantage and they will expand. But if you remove the drug, the energy cost of the pumps becomes a weakness, and instead, the cells that are sensitive to the drug repopulate the tumour.
“We are developing ways to track the population of these different cell types with a blood test that measures tumour DNA that's shed into the bloodstream, and effectively adapt treatments as needed to strike a balance. Our idea is that we can end up using the same drug over and over, treating less often, so fewer side effects for the patient.”
It beats the old paradigm of giving patients the maximum tolerated dose.
“Years of bitter experience show us that rarely works.”
Professor Graham is part of the team, led by Dr Michelle Lockley at the Barts Cancer Institute, who are running a clinical trial called ACTov to test adaptive drug dosing for patients with ovarian cancer.
Taking inspiration from Darwin
Professor Graham takes inspiration from many free thinkers, including Charles Darwin. He recently took his lab to see the former home of Charles Darwin, located in Kent.
“Darwin’s house and garden were full of experiments. He would clear patches of grass and then measure every day, the species as they repopulated the barren earth. I knew he was a brilliant thinker, but what struck me was that he was a real experimentalist as well.”
According to Professor Graham, scientists have mountains of data at their fingertips, very much more than Darwin ever had, and the next big discoveries depend on us creating the tools to make sense of it.
“We have so much data, and the issue is not really generating more data, but it's making sense of the data that we already have. With the right mathematical and computational tools, we can discover nuggets of critical information that are hidden in the data.
“Models of cancer are improving so that we can input measurements – for example, mutational signatures within a tumour at just a couple of snapshots in time – and reproduce the pattern of complexity that we actually observe in the real world.”
The room for experimentation has exploded.
“I feel very passionate about trying to use our understanding of evolution to make a difference for people affected by cancer. Harnessing big data and mathematical models, together with careful experiments, will be crucial to making progress in bringing forward new treatments and detecting cancer earlier.”
Professor Janet Shipley, Head of the Division of Molecular Pathology said:
“We are really looking forward to welcoming Professor Trevor Graham to the ICR in the Division of Molecular Pathology and to him taking up the leadership of the Centre for Evolution and Cancer.
“His aim to build computational capabilities to explore evolutionary processes and apply these to drug discovery holds great promise. Furthermore, as cancers’ evolution touches nearly all aspects of research at the ICR, I believe that Trevor’s vision and expertise has tremendous potential to advance our research through creatively forging exciting new collaborative investigations with teams in the Division and across the ICR.”
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