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THE BIG C

“In the future we will live with cancer, not die from it.”

In the UK, right now, you have a 50 per cent chance of being diagnosed with cancer at some point in your life. But what that means – for you, for your family, for your life expectancy – is changing, rapidly.

Words Becky Allen Portraits Anna Huix

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Professor Charles Swanton
Chair in Personalised Medicine in the Research Department of Oncology, and Group Leader of the Francis Crick Institute. His work focuses on the challenges of metatastic cancer.

Cancer touches lives in many ways. Right now, in the UK, 50 per cent of us will be diagnosed with some form of cancer at some point in our lives. But like the cancers themselves, the experience of it is changing, as increasing numbers of us live with, rather than die from, cancer.

Where we once viewed cancer as a single entity, today we know cancers are myriad different diseases. But even this fails to convey their astonishing variety and mutability. For patients this matters, because better outcomes depend on better understanding.

At UCL, researchers are leading the way by going back to basics. The impressive results show how their cutting-edge work is translating into better diagnosis, screening and treatment for the millions of people affected by cancer.

“Cancer is an incredibly complex disease,” says Charles Swanton, Professor of Personalised Cancer Medicine at the UCL Cancer Institute. “Unlike other areas of medicine where you have a limited number of targets that don’t change over time, the problem with cancer is it’s constantly changing, so you’re dealing with billions if not trillions of tumour cells that all differ genetically from one another.”

Swanton studies cancer evolution, because just as prostate and ovarian cancers differ, a tumour today is not the same as it will be tomorrow. “Every tumour starts from a single cell, but the cancer genome is constantly changing,” he explains. “New mutations arise due to cigarette smoking or ultraviolet light, for example, and some mutations confer a survival advantage that allows a sub-group of cells to expand more than its neighbours.”

The realisation that Darwinian-branched evolution occurs in tumours as well as species has crucial implications. It explains why tumours develop drug resistance, and suggests we can design better drugs by targeting mutations in the ‘trunk’ of the tumour’s evolutionary tree. It also means we need to design clinical trials differently.

Which is why TRACERx, a £14m Cancer Research UK-funded study, is not sampling tumours at a single point in time. Instead, it tracks the evolution of lung cancer in 850 patients over nine years. “What’s incredibly exciting for me is that understanding evolution in cancer provides a whole new way of targeting this disease,” says Swanton.

One such target involves using our own immune system to attack cancer. Dr Sergio Quezada leads UCL’s Immune Regulation and Tumour Immunotherapy Lab and his work is revealing further complexity in the cancer ecosystem. Because, as well as evolving like species, cancer cells co-exist with lots of other cells, and this so-called tumour microenvironment has a major impact on the disease.

“If you take a tumour from a patient and crack it open, you don’t only find cancer cells. Most of the time it’s infiltrated by immune cells, including T-cells.” Quezada explains. “The more T-cells you find in a patient’s cancer, the higher the chance that patient has of surviving for longer. Having lots of T-cells in your tumour is a good thing.”

While the immune system can slow tumour progression, a tumour’s very existence means the immune system has failed. That’s because our immune system is extremely destructive and must be very tightly regulated. Cancer exploits this regulatory machinery, preventing the immune system from reacting quickly and strongly enough to eliminate the disease. “My lab studies how tumours subvert and negatively regulate the immune system. We believe that understanding these mechanisms will allow us to develop drugs that switch on the immune response to the tumour,” says Quezada.

Since the 1980s, labs around the world have discovered 10 or so ‘molecular brakes’ in the immune system. Antibodies against two – CTLA4 and PD1 – are already licensed. Quezada and Tusk Therapeutics are co-developing a third – against CD25 – with first use in patients expected in 2019. “It’s super exciting,” he says. “To me, it’s the most beautiful example of translational medicine. We need to understand at a molecular level what a single cell is doing in response to a single tumour cell. That then becomes a system, a microenvironment and a clinical response.”

As well as finding new ways to target cancer, UCL researchers lead some of the world’s largest studies aimed at predicting and preventing the disease. Professor Usha Menon and Professor Martin Widschwendter both specialise in women’s cancers, which account for almost half of cancer cases among women. Despite great progress against cervical cancer, others such as ovarian, endometrial and some breast cancers remain hard to treat.

Cancer exploits the regulatory machinery of the immune system, preventing it from reacting quickly and strongly enough to eliminate the disease

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Usha Menon
Professor of Gynaecological Cancer at the Institute for Women’s Health and Head of the Gynaecological Cancer Research Centre. Her research covers all aspects of ovarian cancer.

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Professor Mark Emberton
Dean of the Faculty of Medical Sciences and Professor of Interventional Oncology. His clinical research aims to improve the diagnosis and treatment of prostate cancer.

“As a gynaecologist, over the years I have diagnosed many women with ovarian cancer. Because there are no good alarm symptoms, women continue to get diagnosed with advanced disease and this has contributed to poor progress in improving survival,” says Menon. “Surgery and chemotherapy work pretty well in early-stage disease, so if we picked it up earlier, we could improve outcomes and survival. That is at the core of all our efforts – developing an ovarian cancer screening programme so that women can be regularly screened and diagnosed earlier.”

Menon leads two massive screening trials, including the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). One of the largest randomised controlled trials in the world, UKCTOCS has involved more than 202,000 women and more than 670,000 annual screens over 11 years.

So far, it shows that compared with no screening, monitoring an individual’s levels of the naturally occurring protein CA125 is significantly better at picking up early-stage ovarian cancer. Menon will discover how this translates to long-term survival when she next analyses her follow-up data in 2019. “On my good days I think we will see a mortality benefit. On bad days I think maybe we won’t,” she says. “But we’re optimistic.”

In FORECEE, a large trial funded by the EU and the Eve Appeal, Widschwendter is leading a team of researchers across Europe to find a way of identifying women who will ultimately develop cervical, ovarian, endometrial or aggressive breast cancers, from epigenetic analysis of their cervical smears. “Our idea is to get a technique or substrate that combines inherited genetic risk factors with those triggered by the environment and which accumulate with age, and use this to guide risk-adapted prevention strategies.” he explains. “It’s a massive ambition, something that other projects haven’t really addressed.”

FORECEE’s strategy is modelled on the reasons underpinning success in preventing cervical cancer, namely understanding what causes the disease (human papilloma virus) and having ready access to the cells where the cancer originates. Widschwendter believes cervical cells can be used to predict a woman’s risk of developing ovarian, endometrial and certain breast cancers, and that preventive strategies – including lifestyle changes and monitoring – can then reduce that risk.

“If we can find a signature that’s modifiable, it will give women an opportunity to prevent cancer in the same way that blood pressure and cholesterol tests identify people at high risk of stroke or heart attack,” he says. “There are a lot of challenges – we’re not hiding those – but it’s a completely new approach that could completely change cancer medicine.”

Another UCL scientist exploiting existing technology for unmet need is Professor Mark Emberton, Dean of the Faculty of Medical Sciences. He works on prostate cancer, a problematic disease because, until recently, it has been impossible to pinpoint the cancer in the prostate. Without this information, men suffer multiple biopsies or removal of the entire prostate gland. Given that most men develop prostate cancer as they age but only three per cent die from it, and that prostate removal often causes impotence and incontinence, better diagnosis and treatment would make a huge difference to patients.

Over the past 10 years, researchers and clinicians at UCL and UCLH have pioneered ways of locating prostate cancers using MRI. “Imaging is tricky because behind the prostate you have air in the rectum, and in front of it you have bone,” explains Emberton. “But we showed that MRI was 100 per cent better than biopsy. In medicine we celebrate 10 per cent improvements in care, so doubling the sensitivity for detection of clinically significant disease from 48 per cent to 93 per cent is unprecedented.”

The ability to locate prostate cancer is transforming surveillance and reducing unnecessary treatment. It’s also creating opportunities for major advances in how we treat the disease. Emberton is currently testing light as a potential treatment for prostate cancer. Patients receive an injection of a photosensitising drug then, working in the dark, light is shone on the cancer using information from the MRI.

Currently awaiting regulatory approval, the treatment could revolutionise prostate cancer treatment. Not only is it reliable and easy to use, it’s cheap and has few side-effects. “It would be a massive transformation for patients,” Emberton concludes. “Prostate removal is a huge operation. You need a robot to do it, and patients spend several days in hospital followed by a long recovery. Now, we can bring someone in, treat their cancer under local anaesthetic, and they get off the table and walk home with virtually no side-effects.”

To find out more about the life-changing work of the UCL Cancer Institute’s 300 researchers, visit www.ucl.ac.uk/cancer

In medicine we celebrate
10 per cent improvements in care, so doubling the sensitivity for detection from 48 per cent to 93 per cent is unprecedented

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