Sunday, April 2, 2017

Grand Challenge

Aiming for the stars? Announcing our plans for a Grand Challenge.

Nearly 100 years ago, Raymond Orteig – a well-to-do New York hotel owner – offered $25,000 to “courageous aviators” to build a plane to cross the Atlantic.

In doing so, he helped change the world. In 1927, after a marathon 30-hour solo flight, Charles Lindbergh landed the Spirit of St Louis in Paris to claim the Orteig Prize.

And it wasn’t the first time the ‘grand prize’ approach revolutionised things. Two hundred years earlier, the British Government’s Longitude Prize had cracked the challenges facing maritime navigation. Just like the Orteig Prize, the breakthrough – this time by a humble watchmaker – jump-started international trade, and changed the face of society.

Crossing oceans – either by plane or boat – is dangerous. Both of these pioneering projects were hugely risky. But in order to achieve big things, you have to take big risks.

Our quest to beat cancer is a feat much more complex than flying a plane over the sea. It’s harder even than going to the moon and back.

But given that one in two people will develop cancer at some point in their lives, we urgently need a breakthrough. So just like Orteig and the pioneers of the Longitude Prize, we want to see if we can offer a prize to make a giant leap forward in cancer.

So, last week, we kicked off our Grand Challenge – a £20 million prize to solve a problem that will revolutionise our understanding of the disease.

It might sound lofty and idealistic, but we think we need this kind risk-taking if we’re to reach our vision of beating cancer.

So, how will it work?

Focusing on the question

The key to a successful challenge is to define the question you’re trying to solve. ‘Curing cancer’ is too big and too vague to focus minds. We need to break the issue down into smaller, more manageable chunks, and frame the question properly.

So last week, we gathered together 100 of the brightest minds in the UK for our first ‘Big Think’ event. These included cancer researchers, clinicians, patients, engineers, physicists, behaviour scientists, epidemiologists, technologists and more from the across the globe.

And, over a day and a half, the teams chewed over some of the biggest issues in cancer. How can we detect it early? How can we stop it spreading? How can we change the way it’s treated? Can we prevent it in the first place? How do we share information about the disease?

The aim at the event – one of two we’re running – is to try to boil the big, intractable set of issues in cancer research into concrete, manageable ‘Challenges’ for further thought and discussion.

It’s the beginning of a new venture for us, and we have no idea where it will lead.

What happens next?

Great minds at work at our first 'Big Think'
Great minds at work at our first ‘Big Think’

Ultimately, we aim to extract from these sessions a series of realistic, achievable ‘challenges’ – statements of intent with clear boundaries.

We’ll analyse the results – we’re expecting hundreds – and group them together into themes and patterns. And then, later this year, we’ll pass the results to our Grand Challenge Advisory Panel to refine them into up to six ambitious, scientifically robust challenges.

We’re incredibly proud of the calibre of people who have agreed to sit on the panel so far, which draws together some of the best minds in science. They are:
  • Dr Rick Klausner, Chief Medical Officer at Illumina and former Executive Director for Global Health at the Bill and Melinda Gates Foundation, who will chair the panel.
    • Three leading cancer biologists: Professor Suzanne Cory, Professor Ed Harlow, and Professor Sir David Lane.
    • The UK’s Chief Medical Officer, Dame Sally Davies.
  • And a leading expert in human genetics, Sir Adrian Bird.
And we will build this panel over the coming months to include more leading thinkers and innovators, from both within and outside the cancer research community.

Over the coming months, they’ll distil the ideas generated at our Big Thinks into four to six key Challenges, which we’ll share with the public for comment, discussion and debate.

And then we’ll invite the scientific community around the world to form collaborative groups from across different scientific disciplines, and submit proposals as to how to tackle these Challenges. The best idea will get £20 million – to be staggered over five years – to carry out the research in their proposal.

A flexible approach

Some of this sounds a bit vague – and it is: it’s the first time we’ve done anything like this, we’ll be running this process flexibly – adapting as we go, and as the ideas emerge.

For instance, the exact number of the Challenges is still up for discussion, as are the precise dates and milestones for the project. This is partly because some of it depends on the nature of the Challenges themselves – some might need more time to refine than others.

But regardless, through this blog and on social media (using the hashtag #CRUKGrandChallenge) we’ll keep the world abreast of our progress across this uncharted territory, as we take what we hope will be a giant leap forward in our understanding of cancer.
Let's beat cancer sooner

In October, 2015 we launched the Cancer Research UK Grand Challenge – a £100m scheme to tackle seven of the biggest challenges in understanding and treating cancer.  
And in a series of posts over the next two months we’ll be exploring each of the seven Grand Challenge questions set by a panel of the world’s leading cancer experts, we set about finding the biggest challenges in cancer research.

The world’s best scientific minds worked together with patients to settle on the major hurdles that need to be tackled to transform the way we prevent, diagnose and treat cancer.

The result is these 7 questions. And our ambitious Grand Challenge award will help find the answers through £100 million of funding for teams of international researchers.

So what are they?

Q1: Grand Challenge one: can we develop a jab to prevent cancer?

Research that unleashes the full force of the immune system on tumours is changing the face of cancer treatment.
But what if the immune system could do more?

Vaccines help us stave off viral infections that were once lethal to our ancestors. And we now know that some cancers are also caused by viruses, triggering life-saving research into vaccines that can treat these diseases and prevent others too (more on this below).

But this question is different. What if we could develop vaccines to prevent cancers in healthy people that aren’t caused by viruses?

A vaccine like this would need to tell the immune system to keep watch for, and eliminate, rogue cancer cells at their earliest stages of development.

To do this, we’ll need to learn a lot more about the complex ways the immune system spots cancer cells. And understand in more detail how cancer can dodge immune detection.

So, our first Grand Challenge is to: develop vaccines to prevent non-viral cancers.

Q2: Grand Challenge two: wipe out cancers caused by the Epstein-Barr Virus (EBV).
Burkitt’s lymphoma cells – a cancer caused by EBV.
Of the viruses that cause cancer, the Epstein Barr Virus (EBV) has emerged as one in need of global attention.

Following work in Africa on a type of lymphoma, EBV was uncovered as the first virus that can cause cancer in humans. Infection with this virus has been linked to increased rates of cancers found at the back of the nose and throat in China and South East Asia. And it’s also responsible for some stomach cancers, and a second type of lymphoma.

Collectively this adds up to an estimated 200,000 new cases of cancer worldwide each year, and more than 140,000 deaths.

So what if we could eliminate these cancers?

To do this, researchers will need to take on EBV from every angle. We’ll need vaccines that can prevent the infection in those who haven’t been exposed, as well as ways to target cells that are already infected.

This could involve different vaccines to treat cancers caused by the virus – some of which are already being developed. And even drugs that could kill infected cells, or those that have already become cancerous.

So, our second Grand Challenge is to: eradicate EBV-induced cancers from the world.

Q3: Grand Challenge three: prevent cancer by studying ‘scars’ in its DNA.
Whether it’s the chemicals in tobacco smoke, or UV damage from the sun’s rays, carcinogens leave ‘scars’ in a cell’s DNA – something researchers call a signature. Each carcinogen is different, marking our DNA in diverse ways. And it’s these genetic faults that may go on to trigger uncontrolled cell growth and cancer.

The traditional approach to uncovering these genetic signatures has been to study groups of people with higher cancer rates, and look for differences in their genetic code.

But what if we could work the other way around, starting with a tumour’s genetic code and finding new faults linked with different causes of cancer? Could this information then be turned into new ways to prevent cancer by knowing the signatures to look out for?

We know very little about the genetic damage caused by things like obesity and varying levels of physical activity, to name just two growing health issues. And with these complex problems, it’s likely that there will be many different signatures that need untangling before we can find out how to tackle them.

So, our third Grand Challenge is to: discover how unusual patterns of mutation are induced by different cancer-causing events.

Q4: Grand Challenge four: how do you tell the lethal cancers from the non-lethal ones?

This question brings together two challenges that are poles apart. Some changes in the body we call ‘cancer’ don’t actually need any treatment, while there are other aggressive tumours that we aren’t spotting early enough.

Prostate and breast cancers can be diagnosed early, but in some cases the tumours detected through tests or screening won’t go on to cause any harm to the patient. But we can’t always tell which these are. So some patients are having unnecessary treatment, which also means unnecessary side-effects.

On the flipside, we don’t have reliable ways of detecting cancers such as lung, brain, pancreatic or ovarian cancers, which can be particularly aggressive and need urgent treatment.
So what if we could tell the difference between potentially lethal and non-lethal cancers, and turn this into more accurate ways of diagnosing them?

To do this, researchers will need a precise understanding of the biological differences between lethal and non-lethal tumours.
Once they have this knowledge we’ll need to know if it can be turned into new ways of spotting these cancers.

For example, we need to find out if there are tell-tale molecules or faulty bits of DNA released into the bloodstream or urine that could be detected with new technology.

So, our fourth Grand Challenge is to: distinguish between lethal cancers that need treating, and non-lethal cancers that don’t.

Q5: Grand Challenge five: build a ‘Google Street View’ for cancer.

We need to do more than just study cancer cells. There is a whole ecosystem of tissues, cells, proteins and molecules out there that support every tumour.

This ecosystem is called the tumour microenvironment, and it’s a bit like a city. It’s built from different types of cells, with structural molecules and proteins for support. There are blood vessels that act like roads into the tumour, supplying nourishment to keep the cells growing. And these tumour roads even serve as escape routes for cancer cells that spread to other parts of the body.

But while we know this world exists, we don’t really understand how all the components interact. It’s a bit like trying to follow the plot of a film by only looking at a handful of photographs.

So what if we could develop an interactive 3D map of all the different parts of the city and how they work? This would be the ‘Google Street View’ for cancer. And it would help scientists find new ways to monitor the dangerous neighbourhoods inside tumours and shut them down.

To do this, researchers will need to take a completely new approach. They will need to find ways to study the city as a whole, not break it down into individual components as we have done before.

So, our fifth Grand Challenge is to: find a way of mapping tumours at the molecular and cellular level.

Q6: Grand Challenge six: target cancer’s ‘super-controller’.

The MYC gene has been a wily foe for researchers since its discovery in the early 80s.

It’s a gene that tells cells to multiply, and is faulty in almost seven out of 10 cancers. And these faults lead to relentless signals telling cancer cells to keep dividing. So attempts to switch off faulty MYC have been the focus of huge amounts of research.

But these studies have shown that the protein produced by the MYC gene is a tough molecule to target with drugs, and we need a new approach.

So what if experts from diverse scientific disciplines could bring some fresh ideas to the table and finally crack the challenge of MYC?

Because MYC works differently to other cancer drug targets, researchers need to understand its shape and how it sticks to other proteins. Interfering with these sticky interactions is notoriously difficult, but progress in targeting other so-called ‘undruggable’ molecules suggests now is the time to try.

So, our sixth Grand Challenge is to: develop innovative approaches to target the cancer super-controller MYC.

Q7: Grand Challenge seven: kill cancer cells using new ‘smart drugs’.

New technology has allowed scientists to engineer smarter cancer drugs that can precisely target and kill tumour cells in the lab. But just doing this in the lab isn’t good enough.

These drugs can use specialised bits of DNA, proteins and other molecules to home in on ‘red flags’ that make these lab-grown cancer cells unique. But the real challenge comes when trying to get these experimental treatments to reach the tumour cells in patients.

So what if we could find innovative new ways to deliver these ‘smart drugs’ to all cells in the body, but only kill the cancer cells?

To do this, researchers will need to find a way to exploit how traditional drugs reach lots of cells in the body, and find ways to apply this to these newer experimental treatments. Once inside the cells, the drugs would only kill the cancer cells by targeting something unique to the tumour.

This is potentially one of the biggest hurdles facing researchers, but there’s so much to gain if it works.

So, our seventh Grand Challenge is to: deliver biologically active macromolecules to any and all cells in the body.
Those are the seven challenges. We can’t wait to meet the teams that will take them on.

Q1: Starting with question one: Can we develop vaccines to prevent cancers that aren’t caused by viruses?

Many of us will be familiar with the idea of vaccines – one of the greatest advances in medicine – which trigger our immune systems to recognise and attack infectious diseases. Vaccines remain the only medical advance to have ever fully eradicated a disease, ridding the world of the smallpox virus.

But the big question is: could a vaccine do the same for cancer? Obviously, cancers aren’t infections – unlike bacteria and viruses, they develop from our own cells, posing a big challenge for our immune system in recognising them as harmful.

Nevertheless, harnessing the power of the immune system to fight cancer has been a goal for scientists for over a century. But it’s only recently that we’ve begun to understand exactly how immune cells (mistakenly) view cancer as a friend to leave in peace, rather than an enemy to destroy. And then harness this knowledge to develop new cancer treatments.

But this has also raised the question of whether we might be able to use vaccines to prevent – as well as treat – the disease.

Immune surveillance

Vaccines work by training the immune system to recognise small, harmless pieces of a disease, so that it can eradicate anything that looks like it in the future. Once convinced that a particular molecule belongs to the enemy, the immune system is forever primed to treat it as hostile.

Vaccines have already been developed against certain forms of cancer that are caused by viruses, such the human papillomavirus (HPV) – which causes cervical, oral and anal cancers. And eradicating cancers caused by the Epstein Barr Virus (EBV) – such as certain forms of lymphoma – is the second of our Grand Challenge questions. So the idea of creating a vaccine to prevent or treat cancers linked to viruses certainly works in theory.
But only three in every 100 cancers in the UK each year are linked to infections. And in these cases the immune system’s target is distinct – it’s definitely ‘foreign’.

Without that ‘foreign invader’, alerting the immune system becomes a lot more complicated.

So the first challenge set by our panel is to take this a step further, and find a way to directly target cells in our bodies in the earliest stages of becoming a cancer. Helping the immune system destroy these abnormal cells before they develop into cancer could not only save lives, but spare thousands from even becoming a cancer patient in the first place.

It sounds incredible – so how might this work in practice?

What do we mean by a cancer jab?

It’s up to the applicants to come up with the best way to tackle this problem, but the rewards could be incredible – Professor Tyler Jacks

Professor Tyler Jacks, director of the Koch Institute for integrative cancer research at MIT in the US, and one of the members of our Grand Challenge scientific panel, is incredibly excited by the prospect of this question.

“To be clear, the point is not to have a one-size-fits-all vaccine preventing all cancers,” he explains.

“Every cancer is different. But I would be happy, I would be thrilled actually, if this question stimulated research that found a set of molecules, probably not just one, which we could develop into a vaccine for people at a higher risk of certain cancers.”

Professor Christian Ottensmeier, a Cancer Research UK expert in immunology at the University of Southampton, shares his enthusiasm. “It’s entirely possible that as a result of this Grand Challenge people will start to look at the puzzle of preventative vaccination in a different way,” he says.

“So I’m really excited about this opportunity, because I think this will make the research community look at this particular question in a way it hasn’t so far.”

But creating a vaccine to prevent cancer is easier said than done, and Professor Jacks sees several important steps that must be overcome, each with its own unique challenges and hurdles. But the biggest, he says, is the first – finding targets for the vaccine that are hallmarks of developing cancer cells.

Spotting cancer before it happens

Finding suitable vaccine targets requires researchers to pinpoint molecules that the immune system can recognise as ‘foreign’. These are known as ‘antigens’.

“We know that cancers develop due to changes in the DNA,” says Jacks. “Some of these genetic mistakes will result in molecules that look completely different to how they should in a normal healthy cell. If we can find which of these mutations are common in certain types of cancer, we might be able to use these in a vaccine against that cancer type.”

Alongside these faulty ‘self’ molecules, researchers have also found that certain forms of cancer produce normal molecules when they shouldn’t, or in far greater amounts than healthy cells. These are known as ‘tumour-associated antigens’. For example, a molecule that’s only made during early childhood and not at all in a healthy adult might be switched back on and produced inside cancer cells to help them grow.

And as well as these faulty or inappropriately produced molecules, there could be an entirely new method for finding the best targets.
According to Ottensmeier it’s difficult to know what the explosion in data generation will lead to.

“Even three to five years ago it was unimaginable that you would even consider making a patient -specific vaccine,” he says.
“But now that’s already a reality with a number of bespoke, experimental ‘vaccines’ in development as treatments.”

Finding the target is just the first step

Once a suitable collection of vaccine targets are found, there would then be a huge amount of work to make sure the vaccine actually worked, and was safe.

Neither of these will be easy. And since the goal is to create something that protects over a lifetime, it won’t be quick either. It could take decades to ensure that a vaccine preventing cancer in the general population truly works.

But rather than going for this ultimate goal, Ottensmeier thinks that a better strategy – and one that might be achievable within the timeframe of our Grand Challenge – could be to identify and begin developing vaccines that could be used among small groups of high risk patients – for example, women with a family history of breast cancer.

“Women with known faults in their DNA are already offered preventative measures,” he says.

For some this may involve a double mastectomy, like the high-profile actress and filmmaker, Angelina Jolie had in 2013.

“But what if we could offer these women a vaccine against breast cancer rather than surgery?” asks Ottensmeier. It’s a tantalising prospect.

The patient perspective

The Grand Challenge that most excites me has to be research into a vaccine to help prevent cancer. Easy words to write – but I’ve probably only a small idea of what a huge undertaking this is. When I was diagnosed with lung cancer with a prognosis of 3 months, I was left wishing I could pop along to my GPs for a cancer jab and it would all be over (we didn’t even have the flu jab then). But that wasn’t to be, and it’s a small miracle that I am still here. Reading through the seven questions put forward I was unsure which one I would like to see a group of scientists take on. But as I looked up from my laptop, stuck on the rim of a shelf, was a yellow sticky note reminding me that I was due for my flu jab that afternoon. Believe me, my selection is not one of divine intervention, rather the simplicity of its use if it was to work.
– Terry, patient panel member for the Grand Challenge

High hopes

Our understanding of the immune system has come on in leaps and bounds in the last decade, and the resulting progress in immune-based treatments has made things possible that were previously considered completely untenable.

So, in a period of such rapid progress, Professor Jacks argues: “Why not reach for the stars a little bit here”.

“A Grand Challenge should be challenging, and shouldn’t be obvious. It’s up to the applicants to come up with the best way to tackle this problem, but the rewards could be incredible if successful.”

And being on the cusp of discovery is exactly how this type of research should be carried out. “Honestly, we just don’t know if we can do this,” he says.

“But failure in research is commonplace. We make progress despite a great deal of failure.

“If you don’t try, you’ll never succeed, and just because it might not work is no reason not to try.”

Q2.Grand Challenge two: wipe out cancers caused by the Epstein-Barr Virus

The Epstein-Barr Virus (EBV) is one of the most common viral infections in humans – around 19 in every 20 adults carry the virus. In terms of the sheer number of people infected, it’s one of the most prolific viruses the world has ever seen.

And in most of us, it appears to cause no harm at all.

But there’s a sinister side to the virus too. In some people, it can cause cancer.

In fact, EBV was the first virus found to cause cancer in humans. We now know that, every year, EBV infections trigger 200,000 new cases of cancer – and more than 140,000 deaths – worldwide.

These are mainly certain forms of lymphoma, as well as cancers that start at the back of the nose and throat (the nasopharynx), and some cases of stomach cancer.

Molecules produced by EBV can send infected cells into overdrive, telling them to keep dividing.  But diet, genetics and exposure to other infections also play an important role in cancer developing.

This dark side to what’s a relatively common infection has been felt in some parts of the world more than others. China and parts of South East Asia have seen increasing rates of those cancers affecting the nasopharynx, while rates of EBV-linked lymphoma have hit certain parts of sub-Saharan Africa in particular.

And while expert teams dotted around the globe have chipped away at the challenge of tackling EBV-linked cancers, some believe the geographical spread of these cancers – hitting mainly the developing world – may have stifled interest in studying them.

Now that could be set to change.

A defined and achievable goal

Professor Sir David Lane – Scientific Director of the Ludwig Institute for Cancer Research, Chief Scientist at Singapore’s Agency for Science, Technology and Research (A*STAR) and one of the members of our Grand Challenge Advisory Panel – believes that understanding the trigger behind these tumours actually gives us a real chance of tackling them.

These cancers have a known cause: a virus. And we have a long and successful history of dealing with viruses – Professor Sir David Lane

“One of the exciting things about this challenge is that it has a very defined – and in my opinion achievable – goal,” he explains.

“These cancers have a known cause: a virus. And we have a long and successful history of dealing with viruses – either preventing people being infected using vaccines, or successfully treating infections.

“There’s no reason we can’t do the same with EBV.”

Lane sees the attempt to stop people becoming infected in the first place, for example through vaccination, as a key focus for this challenge.

“There’s a precedent with the success story of vaccines against the human papillomavirus (HPV), which causes several types of cancer, notably cervical cancers,” he says.

HPV vaccines began their development in the early 1990s and were rolled out as part of a national programme to immunise schoolgirls in the UK in 2008. The vaccination programme is predicted to save thousands of lives in the future.

And finding a similar way to prevent EBV infection could stop cancers caused by the virus developing, and save lives.

But for Lane, there are potentially even bigger benefits ahead – and it’s not just about vaccines.

“There are definitely some cancers we know are caused by EBV. But science is an ever-moving field, and there may be other cancers linked to the virus we don’t know about yet.”

“One theory is that fighting the infection could exhaust or dampen down our immune response, which might help other types of cancer escape immune destruction,” says Lane.

“The important point is that the solution isn’t necessarily a vaccine. There may be ways of uncloaking the virus to immune cells, helping people get rid of the infection themselves rather than having low level infection for years – sometimes their whole lives.”

‘It’s not been lack of ideas that’s held us back’

Research into EBV-linked cancers has been ongoing for 50 years. And there are a lot of scientists with in depth knowledge of the virus.

But Lane believes that up until now, it’s lacked the momentum that’s needed to turn research into new ways to tackle the disease.
The Grand Challenge would be a significant boost to the efforts of the vaccine research community
– Professor Alan Rickinson
“We’ve had a patchwork of researchers dotted about the world, but no real large, united front to tackle this head on,” he says.

“And this is where the Grand Challenge could really turn the tables.”

One of the scientists leading the charge is Professor Alan Rickinson, a Cancer Research UK-funded world leader in EBV research.

He believes that some of the reasons why an EBV vaccine hasn’t progressed as far as it could have are a lack of political will and limited backing from the pharmaceutical industry.

“It’s not been lack of ideas that’s held us back,” he says. “We’ve long had the goal of developing a vaccine to protect people from becoming infected with the virus. And the success of the HPV vaccine is a shining example of what science can achieve.”

But viruses are very different from one another, and the development of the HPV vaccine doesn’t automatically mean it will be simple to make an effective EBV vaccine too.

That’s because EBV is very different from HPV. EBV is a type of virus called a ‘herpesvirus’, and at the moment, there are no protective vaccines against any human herpesviruses.

“An EBV jab would be a first,” says Rickinson, “and a very important first!”

“The Grand Challenge would be a significant boost to the efforts of the vaccine research community.”

Beyond the vaccine

But while a vaccine would be a big step forwards, there’s also an urgent need for better treatments for the 200,000 patients diagnosed every year with EBV-linked cancers.

Dr Emma King, a leading head and neck surgeon at the University of Southampton, is carrying out clinical trials testing new ways to boost the immune response against cancers, many of which are caused by the HPV virus.

“A huge number of cancer cases worldwide are caused by viruses,” she explains. “And one of the big questions we still need to answer is why some people’s immune systems recognise and get rid of viruses, while other people can’t clear the infection and are at risk of developing cancer.”

According to King there are several key factors that might play a role – the virus, other infections the immune system has to cope with, lifestyle factors, and of course our genetics.

She believes that curing these cancers will need a multi-pronged attack, and this may differ between patients. For example, it could involve combining a vaccine with a drug that stops cancer cells hiding from immune cells, or combining radiotherapy with immune boosting drugs.

“Every step is a step in the right direction,” she says. “But science is expensive, and the Grand Challenge will help boost progress by bringing together experts from different fields, helping us learn from each other.”

The patient perspective

As a patient representative I’ve always struggled with the many acronyms within the projects I’ve been involved in. Going back and forth until they are fully ingested reminds me of when I was a youngster at school learning my lines for the school play. Reading question two of the Grand Challenge another acronym for a cause of cancer pops up – EBV- Epstein-Barr Virus. As with the first challenge, developing a vaccine could be the answer for preventing infection with EBV. But as with all of the Grand Challenge questions it’s more complex, requiring a change in the way research is usually done. Throughout the Grand Challenge workshops I could hear the positivity in the talks given by the scientific community, the freedom of expression used by the presenters was open and cavalier. A world apart from the safety that one might feel when your colleagues all understand the acronyms. ‘Imagine’ was a much used word, along with ‘Reach for the stars’ and ‘If we don’t try we’ll never succeed’.  The cancer world is full of acronyms, an ABC of symptoms, causes, types, and treatments. There are no acronyms for cure. Taking on a challenge with this attitude and breaking out of the comfort zone of acronyms is exactly what’s needed to eradicate EBV-induced cancers from the world. 
– Terry, patient panel member for the Grand Challenge
Research has revealed a lot about EBV – and other viruses linked to cancer – over the past 50 years, but the story is just beginning. The viruses themselves are only part of the picture; our genetics and environment also combine to play a role in cancer developing.

But with all the knowledge we have, curing, or preventing, EBV-linked cancers seems within reach – it just needs that investment to make it a reality. And the Grand Challenge could provide exactly that.

“The whole idea of a ‘Grand Challenge’ is tremendously exciting,” says Lane. “It’s a different way of doing research. It brings scientists across the world together and approaches these large problems by combining a wide breadth of skills, knowledge and technology.”

And with the potential of saving 140,000 lives a year across the world, it will certainly have a big impact.

Q3: Grand Challenge three: prevent cancer by studying ‘scars’ in its DNA

The third of our Grand Challenge topics asks: can we prevent cancer by studying ‘scars’ in its DNA?

If you’ve read the news recently, you may have stumbled across an ongoing debate about whether cancer is caused by ‘bad luck’, or by the choices we make during our lives.

The reality, of course, is that it’s both. But the answer to the simple question ‘what causes cancer?’ depends on who you ask.

Researchers from a branch of science called epidemiology, who study disease trends across whole populations, would point to things like smoking or obesity – because their studies have shown that some cancers are more common among people who smoke or are obese.

And we now know that as many as four in ten cancers are linked to what epidemiologists collectively call ‘exposures’ – either well-known things like chemical carcinogens in tobacco smoke, or more complex processes  like ‘a poor diet’, which is much less well understood.

But if you ask the laboratory-based biologists, who study cells’ inner mysteries, they’d probably talk about things like DNA, genes and mutations. From this point of view, cancer is caused when the genetic programming in our cells gets corrupted.

Clearly both answers are true. And thanks to decades of research, we know a fair bit about how the machinery inside our cells can go catastrophically wrong, and that things in our environment – so-called carcinogens – can make this more likely.

But there are some crucial missing pieces in this jigsaw puzzle.

On the one hand, we simply don’t know exactly how some of these things cause cancer – particularly ‘lifestyle’ factors like obesity or excess alcohol consumption (although we do have decent theories for some of them).

On the other, large studies looking at countless thousands of patients’ tumour DNA have started to find scores of patterns – the scars left on our genomes as cancer develops. And with a few notable exceptions, most of them are of unknown origin.

So the third of our Grand Challenges is to try to make significant headway in uncovering vital new links between the processes in our cells and the way our environment affects them – both to better understand how cancers arise and, crucially, to prevent them in the first place.

‘Reverse epidemiology’

As Harvard Medical School’s Professor Ed Harlow – a member of our Grand Challenge Advisory Panel – tells us: “Epidemiology typically starts by looking for patterns in the distribution of tumours – where they occur in the population – and then uses those patterns to do detective work to figure out what might be the cause.”

This conventional approach has resulted in some “spectacular” findings, he says, identifying many of the important causes of cancer, such as smoking or UV radiation.

“But over the last few decades – and particularly the last couple of years – we’ve see the appearance of another type of approach, that focuses first on the characteristics of tumours themselves, and uses those as a clue to search for what the cause might be.”

“So the idea that you might be able to find new carcinogens by this method caught the Grand Challenge panel’s attention. We thought, ‘oh yeah, we’ve got to do that’.”

And Harlow thinks the approach has the potential to transform how cancer development is understood.
We thought, ‘oh yeah, we’ve got to do that’.
– Professor Ed Harlow
To show how powerful it can be, he recalls the story of aristolochic acid, a powerful cancer-causing chemical found in certain plants – including those used in certain traditional Chinese medicines.

In 2012, researchers studying a rare form of bladder cancer found a suspicious pattern of mutations in tumours from those who’d taken these medicines – effectively a fingerprint of the damage the chemical in them had wreaked inside the patient’s cells.

But the researchers subsequently found the exact same fingerprint in the DNA of some patients’ liver cancers too – a form of the disease not previously linked to aristolochic acid exposure, and giving renewed urgency to efforts to enforce bans of medicines containing it.

So identifying these patterns can lead to clear ways to prevent cancer. Can we find more?

Work in progress

One of the labs making big inroads is the Wellcome Trust’s Sanger Institute in Cambridge, UK. As researchers around the world have begun to publish reams of cancer DNA data, a team at the Sanger led by Dr Serena Nik-Zainal has been combing them for underlying patterns.

They started back in 2012 by looking in breast cancer, “a cancer type known not to have clear environmental associations,” she says. “We wanted to see whether we could make sense of the vast mountain of mutation information that we would get from large numbers of samples.”

“We were heartened by unearthing 5 signatures in this single cancer type alone.”

This led to further studies, in more types of cancer. “We’ve now identified 30 signatures in around 40 different cancer types. Some are associated with environmental exposures like UV radiation or aristolochic acid. Others are associated with problems inside cells, like defective DNA repair pathways, or the action of certain enzymes.”

But the vast majority, she says, are of completely unknown origin.

Professor Laurence Pearl, from the Genome Damage and Stability Centre at the University of Sussex, and one of Cancer Research UK’s leading experts in understanding how cells repair damaged DNA,  has been keenly following the Sanger team’s progress.

“You look at some of the patterns Serena’s team have discovered and think, oh, that’s clearly caused by faults in one or other of the processes we’ve known about for some time,” he says.

“But for others, we’ve all been scratching our heads trying to think what failure – or sequence of failures – could cause them. Understanding what’s going on has eluded us to date.”

Grand Challenge 3 gif2

A broad coalition

As well as the obvious strategy of playing ‘match the pattern to the carcinogen’, the Grand Challenge panel is hoping to see these sorts of efforts scaled up considerably, and broadened in scope – Harlow says he’s keen to look beyond mistakes in the sequence of ‘letters’ in the cancer’s DNA, for even wider patterns in how entire chromosomes or even cell types are organised.

“There’s a general call in this Challenge to say ‘look for new patterns,’ patterns that are inherited from tumour cell to tumour cell,” says Harlow. “If they are unique, or different – or even just found much more commonly in certain types of tumours – then that must mean that there’s some reason. Let’s go back and see what it is.”

So while looking simply for the action of carcinogenic chemicals is a “clear, relatively easily understandable first step,” Harlow thinks it might also lead to things we don’t understand at all at the moment.

And this, he says, will need expertise from a whole range of different scientific traditions.

Laurence Pearl (via wiki commons
It’s very, very difficult, but certainly not impossible – Prof Laurence Pearl  

“Starting at the beginning, if you identify a carcinogen [by analysing DNA patterns] you’d want to know the steps between exposure and actual changes in the DNA.

“So you’d need biochemists, cell biologists and systems biologists to be part of that discovery process, to try and learn what that pathway is. Then, if you’re thinking about mechanisms of prevention, you might bring in whole other types of scientific expertise too.”

And ‘traditional’ epidemiology has a vital role to play too: “Having people who think about the actual incidence of disease might be an interesting group to add to mix too, to point out places where it would be more interesting to look,” he says.

Pearl and Nik-Zainal agree. “You need a team with the capability to track how these changes emerge in tumours over time,” says Pearl. “It needs a really broad set of skills – not just geneticists, although you need them too. It’ll be a fascinating challenge. It’s very, very difficult, but certainly not impossible.”

This combination of cross-disciplinary experts “would permit systematic, large-scale studies that could propel the understanding of signatures further and faster,” says Nik-Zainal.

But there’s also a geographic angle to this. Different regions of the world are affected by different types of cancer – and this is likely due to differences in lifestyle, environment, and genetics. So Harlow is keen to stress that the Challenge needs international input too.

“The broader you build your database of cancer DNA sequences, the greater chance you have to find patterns of interest. So more groups, and more information, gives you a much broader starting point, but it also changes the kinds of exposure and the kinds of cancer-causing events that might be picked up,” he says.

The Patient Perspective

I don’t have a science background, but I do know from my life experience that the best way to handle difficult situations is to ensure, as best you can, that they don’t arise in the first place. It’s a simplistic view, but it would be fantastic if we could this with cancer. For me, the attraction of the Grand Challenge is that it is most definitely not “business as usual.” At the session I went to in Edinburgh it was noticeable that even some very seasoned and well-published researchers were finding it challenging to think ‘big’ and remind themselves that this is not a routine grant-funding exercise. In my book, preventing cancer is the biggest challenge of all and the one with the biggest potential in terms of positive outcome, not just for patients, but for society as a whole. This is an exciting prospect, which means that, if the challenges are met, patient benefit should be on a very large scale.
– Peter, Grand Challenge patient panel member

Prevention is better

The ultimate aim of the Challenge, says Harlow, is to try to find ways to prevent people from developing cancer – whether it’s by identifying rare, potent carcinogens, or a better, deeper understanding of how our lives affect our genomes.

“There are ‘knowns’ that we could get from this that are very valuable, but the chances of uncovering something even more powerful, but unknown, seems to me to make this a very exciting opportunity.

“There are all sorts of things about how we live our lives that we don’t understand in great molecular detail yet. And I can imagine there could be something out there that we could find that would be eye-opening and completely astonishing to all of us.

“And I don’t know whether that will happen – but it certainly should be something we should aim for.”

Q4: Grand Challenge four: how do you tell the lethal cancers from the non-lethal ones?

The fourth of our Grand Challenge topics asks: can we spot the potentially lethal cancers that need treating, and non-lethal ones that don’t?

The word ‘cancer’ tends to conjure up the idea of an aggressive disease, which grows rapidly, spreading around the body and that ultimately kills if not treated.

But this isn’t always the case. Some things that are diagnosed as ‘cancer’ can grow so slowly that they may not even cause harm in a person’s lifetime, and so don’t need any treatment.

The problem is that at the moment we can’t tell the difference between these slow growing cancers and the aggressive ones.

This ‘overdiagnosis’ is a big problem. We’ve written about it in the context of breast cancer screening before, but it’s also a big issue in prostate cancer, where we often hear about ‘tigers’ (aggressive cancers that can spread and kill) and ‘pussycats’ (slow-growing tumours that wouldn’t cause an issue in a man’s entire lifetime). And over-diagnosis is increasingly being linked to other types of cancers too.

But we also have issues detecting some of the most aggressive types of cancer early enough, meaning we only find them when it’s often too late to tackle them.

So our fourth Grand Challenge is all about delving deeper into cancer’s biology to solve two of the most important mysteries in medicine – how to tell the difference between the cancers that can kill and the slow-growing forms of the disease that don’t, and how to track down the cancers that stay hidden until it’s too late.

“This grand challenge is critically important,” says Professor Brian Druker, member of the Grand Challenge Advisory Panel and director of the Oregon Health and Science University Knight Cancer Institute in the US.

“We know that cancers are easier to cure if they’re found early – that’s clear for every type of cancer. But the next issue is whether our early detection tests are really what we want them to be right now.”

Harm vs. Benefit

The impact of ‘over-diagnosed’ cancers can be life-changing and unnecessary – causing people the stress and anxiety of a cancer diagnosis, and all the downsides of treatment, including potentially serious side effects.

“As we get better at detecting cancer, we’re also finding early cancers that don’t need treatment. And then comes the question of whether we’re doing more harm than good by treating these cancers,” says Cancer Research UK’s Professor Peter Sasieni, an expert in cancer screening and epidemiology.

“At the moment there’s a bit of a balance, because despite there being clear benefits, there are also definite harms. But if we were able to identify cancers that don’t need treatment, it would mean the benefits of better detection would out-weigh the harms.”

We still want to detect cancers early when they’re most curable, but not subject patients to unnecessary treatment if they don’t need it. We want things that are extremely accurate – Professor Brian Druker

Another crucial breakthrough would be the ability to find aggressive cancers (like pancreatic, lung, brain and ovarian cancers) sooner which are often deadly because they’re hardest to treat when found late. These cancers, too, can also be difficult to tell apart from more harmless lumps on scans and other tests.

According to Druker, technology has a big part to play.

“We’re trying to meet in the middle of these two issues, so that we have much more accurate technologies to help us treat patients appropriately,” he says.

“We still want to detect cancers early when they’re most curable, but not subject patients to unnecessary treatment if they don’t need it. We want things that are extremely accurate.”

Researchers haven’t been able to do this before, because of a lack of knowledge of the biological differences within a certain type of cancer, and how these differ from earlier, pre-cancerous changes they can arise from.

Thankfully, over the last decade or so, there’s been an explosion in new technologies that can analyse our genes in great detail, extract tumour cells and DNA from our blood, and study the proteins in our body and what they do in unprecedented detail.

And alongside our deeper understanding of cancer biology, these technologies now stand us in good stead of overcoming this grand challenge.

“We want a team of biologists who understand what distinguishes a lethal from a non-lethal cancer, combined with a group of technology experts who can find the right technology to apply to this,” says Druker.

“When you look at many scientific advances, it’s often when you get different areas of research or technology coming together that you see dramatic breakthroughs.”

An advance of this kind could not only save lives from aggressive cancers by finding them earlier, but also reduce the harm caused by treating people with cancers that will never cause them any problems.

This, in turn, could lead to great improvements in how we screen for cancer, by helping us understand what to do with overdiagnosed cancers.

Re-branding cancers

But there’s also a second challenge waiting for us if we get this right. ‘Cancer’ is a hugely emotive word. The idea that some cancers don’t need treating is a hard one to get your head round. How would people respond to being told that their cancer was safe to live with and won’t need treating?

Professor Druker sees this as an important issue when discussing such tumours: “We have to stop calling things that are non-lethal ‘cancer’, because if a doctor says you’ve got cancer you’re going to want to get rid of it. As soon as you say ‘cancer’ people get worried, so we’ve got to come up with a different name.”
"While many cancers will still need prompt treatment, we will get to a place where we will be able to confidently say that others won’t ever cause harm, so don’t need treatment
– Professor Peter Sasieni
Some scientists have already looked at ways to tackle this problem. Dr Laura Esserman and colleagues propose the term ‘IDLE’ (which stands for ‘Indolent Lesion of Epithelial origin’) to describe non-lethal tumours.

She argues that doctors must lead the way in changing how people think about cancer, increasing awareness of IDLE tumours and how they should be dealt with. And that our one-size-fits-all approach to naming cancer isn’t suitable now we know there are lethal and non-lethal versions of the disease.

“Science has taught us quite a bit about the disease in the last few decades, so a one-size-fits-all definition is no longer the right fit because there isn’t just one type of cancer – there are many,” she told CNN back in 2015.

“It’s like allergies; we can easily understand that there is more than just one type of allergy. Allergies vary hugely in type and severity, and not everyone will lead to anaphylactic shock or a fatality.

“Some allergies cause no more than itchy eyes or a runny nose. The same principle is true of cancer. And because the term cancer is surrounded by connotations of panic and death, in the case of extremely low-risk lesions, we should reclassify them accordingly.”

The patient perspective

I think the encouragement and freedom that research teams will be given by the Grand Challenge is really exciting. From my experiences of cancer I’ve seen people diagnosed early but still die of their cancer, while others have been diagnosed late and survived. Early diagnosis is vital to improve survival, but it’s not enough to just detect cancer early – we also need to be able to recognise the lethal ones that need treatment. This encompasses complex science along with changing people’s perceptions of cancer too, which makes it fascinating. In other words, there’s the technical challenge to find ways of distinguishing lethal from non-lethal cancers – which is challenging enough in its own right – but then that has to be put into practice. I hope that research teams can draw inspiration from that to do something incredible.
–  Jim, member of the Grand Challenge patient panel
A change of this kind would have a huge impact in both how society views cancer and how doctors treat it – in all of its guises.

As Professor Sasieni contemplates: “Eventually I suspect that – while many cancers will still need prompt treatment – we will get to a place where we will be able to confidently say that others won’t ever cause harm, so don’t need treatment.

“But they wouldn’t be what many people think of now when they hear the word ‘cancer’ – and certainly not the death sentence that people thought of 40 years ago.”

Q5: Grand Challenge five: build a ‘Google Street View’ for cancer

The fifth of our Grand Challenge topics is posing the question: can we develop a ‘Google Street View’ for cancer?

‘You have reached your destination’: five words that have become synonymous with how technology helps us get around.

And whether it’s via satellites orbiting earth or small cars carrying cameras, complex digital mapping has made navigating our world much simpler. With a few taps of our fingers we can zoom in on our nearest post office, or out to the borders of continents.

For years researchers have used fancy microscopes and scans to map tumours in similar ways, hoping that this could reveal new avenues to treat the disease.

Alongside this, scientists have also meticulously broken tumours down to study the masses of cells that form the rogue ‘towns’ and ‘cities’ that make up cancer.

These two different research worlds have led to big strides in the ways we both diagnose and treat cancer. With the latest imaging techniques, doctors can see the size of a tumour, helping to plan procedures like surgery or radiotherapy.

And with samples of cells (biopsies) we can begin to understand the faulty molecules that have led groups of cells down the path towards cancer, pointing to those which could also be the targets of new treatments.

But putting all this complex information together in enough detail has been tough. Our map isn’t complete. We can see the border of the city, but we have no idea how the different boroughs within it are connected. And while we know there are bad neighbourhoods, pinpointing the rogue cellular communities and understanding how they corrupt their neighbours has been just out of reach.

Our fifth Grand Challenge hopes to change that.

Through a combination of next-generation technology, and expertise ranging from physics and maths to biology and computing, we want to build the ultimate map of cancer.

A new type of organ

“We’ve recognised for a long time that a tumour isn’t just a collection of cancer cells,” says Dr Rick Klausner, former Director of the US National Cancer Institute and chair of our Grand Challenge Advisory Panel.

Instead, he sees a tumour as much more like an organ, growing from our own cells gone bad.

“For a century, all of our scientific research has aimed to describe cancer by isolating the cells,” he says.

“That makes perfect sense. And we’ve made great progress.”

But in the background, says Klausner, we’ve always known that to truly understand how the disease behaves, we need to see it as an organ.

By working with isolated samples, researchers are actually measuring an average of the genes and faulty molecules inside it, potentially missing some of the finer details about how the cells carrying these faults work. So while they have been aware of the scale of the problem, the technology has been missing to fully understand it.

Rick Klausner
Imagine it like a map of a country you were trying to attack. There’s an army somewhere in the country, and you know that some people in the army are carrying guns. But, most importantly, you don’t know exactly where they are – Dr Rick Klausner

“The reality is the vast majority of our technologies in research involve measuring molecules in bulk,” says Klausner.

“What we do is we measure the total amount of say, DNA, or the total changes in DNA in a tumour. The tumour, with all of its cells and all of its neighbour relationships, is lost. We do everything to lose the mapping, and we just ask what the total content is.”

He likens this to the logistics of warfare: “Imagine it like a map of a country you were trying to attack. There’s an army somewhere in the country, and you know that some people in the army are carrying guns. But, most importantly, you don’t know exactly where they are.”

In terms of cancer, you might imagine that the soldiers carrying weapons are the more aggressive tumour cells that we need to understand and target. Without knowing where they are we can’t truly understand how they work, and also collude with other cells.

So the challenge is to find a way to accurately measure the size of an army’s arsenal – the combination of faulty genes and molecules that may fuel a tumour’s growth a spread – while also taking stock of where it’s located within the tumour’s ever-changing terrain. And, crucially, Klausner is confident that the latest technology is now able to start homing in on the challenge.

“We have the beginning of technologies that allow us to look at all these aspects of the organ without destroying its structure,” he says.

And he offers a tantalising glimpse of what this technology could uncover. “I think there’s a great chance that we’re going to discover that, in tumours, there are types of cells that today we don’t even know exist in our body.”

Klausner speculates that these could be: “normal cells that have been re-educated and changed by the tumour itself. The value of this would be extraordinary”.

But you can’t draw a map without looking at the terrain. And being able to measure the extent of an army’s arsenal only answers one part of this challenge.

It’ll take new ways of looking at tumours – through advanced microscopy and scanning techniques – to help pin down the locations.

A new revolution

“If you think about the history of medical imaging and its use in the clinic, we’ve been quite good at adopting new technologies,” says Dr Sarah Bohndiek, a physicist and expert in cancer imaging from our Cambridge Research Institute. “For example, ultrasound was developed following the use of sonar in the First World War.”

And according to Bohndiek, it’s thanks to this post-war revolution that we have the tools we need to gather images of a patient’s entire body. For cancer, this has offered a clearer picture of where a tumour is, which is vital for surgery and radiotherapy. But that picture could be telling us more. And Bohndiek predicts we’re on the cusp of a new revolution that could give us the answers.

“We’re now having a second revolution, which is imaging particular areas of tumours or cells at very high resolution,” she says.

“Now we can look within single cells and see individual proteins interacting, and see the DNA being made.”

And being able to view cancer on two very different scales – where the tumour is in the body, and what’s going on inside its cells – means we have a much better chance of mapping a tumour’s inner workings.
"We’re now having a second revolution, which is imaging particular areas of tumours or cells at very high resolution
– Dr Sarah Bohndiek
“We have our whole body imaging that we would classically think about in the context of cancer,” says Bohndiek, “and we also have these microscopy approaches, which can be applied to single cells and zoom right in.”

Combining these technologies could put the missing layer of the map within reach. “We’ve not been able to connect these bits of information before,” says Bohndiek. “And I think now is a great time to try.”

But there are some big technological hurdles ahead. “Imaging is always a massive trade-off,” she adds.

To understand why, imagine zooming in and out of the map on your smartphone. If you zoom in you can see each house on a street, but you can’t see where that street is located in the city. Equally, a city-wide map won’t be able to tell you the colour of the door at number 65.

“You’re either trading off your sensitivity, or you’re trading off your spatial resolution, or you’re trading-off the measurements you can make over time. You can’t really have everything, and that’s one of our biggest challenges,” says Bohndiek.

One of the key things that scientists need to overcome is settling on exactly which information is most useful. And putting that together will require some expertise in handling big data.

Big data

“The quantity of data is certainly a problem,” says Dr Andrew Steele, a computational biologist from the Francis Crick Institute in London.

Steele and his colleagues are used to handling vast amounts of genetic data, mining it for clues about what might trigger cancer and other diseases. They focus on all three billion letters of genetic code we call the human ‘genome’. So the team is all too clear on the data challenges this brings.
"In the background to all this, although it’s nice to think of it as a Google Street View, it’s a Google Street View of a very rapidly changing town"
– Dr Andrew Steele
“Say there’s a genome for each sample, and say that genome is approximately the same size as a normal human genome, every single one of those samples is going to be a gigabyte of data before you even start,” he says. “That’s a lot.”

According to Steele, the challenge will lie in understanding what’s changed in a tumour compared to its healthy surroundings. But he believes that connecting together data that covers the differences between cancer cells, healthy cells and even the cancer cells themselves “is as much a conceptual challenge as it is a computing one”.

“You want to create a map that somehow explains what the cancer’s doing and how the genome connects to that. That’s going be very, very challenging I think.”

“In the background to all this, although it’s nice to think of it as a Google Street View, it’s a Google Street View of a very rapidly changing town,” he adds.

But there’s no better time to try and build this map. From a technological and a financial perspective, reading all the genetic information held within a cell’s DNA has never been easier or cheaper.

“The cost of DNA sequencing has plummeted, as has the computing cost of processing that data” says Steele.

“Where previously you’d be lucky to have a DNA sample from a person’s tumour, now it’s potentially cost effective to analyse multiple samples from different parts of a patient’s tumour at different times during the cancer’s progression. And that’s just something that wasn’t financially possible before.”

The patient perspective

We won’t understand how tumours function until we understand why all the cells are there, how they got there, and what they are doing. At the moment the picture we have is fragmented. This challenge encompasses so much science, involving technology across disciplines. Everything has to work together for this challenge to be successful. Being part of the Grand Challenge is the icing on the cake for me. Not only do I have the opportunity to hear what the challenges are, but also to explore innovative solutions. From the patient and public perspective we often have insights and expertise that complement and add value to the research. We have ideas that can relate the research to problems faced by patients and the wider public; or ideas for improving how the data is collected, analysed or reported. There is nothing as important as ensuring that the patient voice is heard.
– Helen, member of the Grand Challenge patient panel
The prize for successfully combining the technology and data is huge. “If this works, this is what all clinical pathology labs will look like. These are the tools they will be using in the future,” says Klausner.

And to do this, it will take experts from across multiple scientific disciplines.

The right people

“The research community will have to come together,” says Klausner. “We need to evolve our machinery, evolve our technology.”

“It’s about getting the people that are fantastic at imaging together with people that know how to measure molecules, and with the technologists that know how to read RNA, DNA and protein, and the specialists in cell biology, cancer biology, immunology, inflammation.

“That’s the great thing about these challenges. We will discover the true life of a tumour, which we haven’t ever done before.”

Getting this right will bring our destination into sight. And solving this challenge will help plot the routes we need to take to reach it.


Q6: Grand Challenge six: target cancer’s ‘super-controller’

The sixth of our Grand Challenge topics is posing the question: can we target the cancer ‘super-controller’ MYC? 

Researchers already know how to theoretically cure a significant proportion of all human cancers. The problem is actually doing it.

At the heart of this challenge lies a molecule called MYC. In the same way that a conductor directs all the various parts of an orchestra to work together in harmony, MYC co-ordinates the actions of many different genes inside cells to keep things running smoothly.

From controlling cell division and growth, to instructing faulty cells to die, MYC has been linked to a wide range of fundamental biological processes – something we’re written about in depth in this post. And, unsurprisingly for such a ‘super-controller’, faults in MYC have been linked to many different types of cancer.

Researchers have long known that faulty, overactive versions of MYC can lead to cells dividing out of control – like a conductor whipping an orchestra into a chaotic, frenzied crescendo – ultimately leading to cancer.

In fact, overactive MYC is found in up to seven in 10 tumours of all kinds, from aggressive lung cancers to childhood brain tumours. As a consequence, researchers around the world have focused a huge amount of effort on trying to switch it off.

Unfortunately, switching off MYC is turning out to be an enormously complex puzzle. And that’s why we’ve set the challenge of solving it.

Switching MYC

MYC bound to DNA
MYC (purple coils) bound to DNA. Public domain, via Wikimedia commons.

Although researchers have known about MYC since the 1980s, the fact that it does so many different things inside cells means it’s tended to be overlooked as a target for cancer drugs,. Surely, the argument goes, it’s impossible to hit MYC, and stop cancer cells dividing, without also messing up all the other vital processes it’s involved in?

But in the past five years or so, a team of Cancer Research UK-funded researchers in Cambridge have proved everyone wrong.

Using genetic engineering techniques, they’ve created mice whose MYC gene could be specifically switched off throughout their whole bodies. When these animals developed lung cancer, turning off MYC completely killed the cancer cells. Importantly, the treatment only caused mild, reversible side effects, suggesting the impact of temporarily blocking MYC in the rest of the body – which is what would happen with a drug – might not be as severe as was first thought.

These remarkable results re-ignited interest in targeting MYC as a potential cancer cure. But the system that Cambridge team used relies on complex genetic engineering – something that’s not technically or ethically possible in humans – and the hunt is on to find drugs that can stop MYC in its tracks.

But it’s not a simple task, as our chief scientist, Professor Nic Jones, tells us: “All the evidence would suggest that MYC is a good target, and there have been efforts to develop drugs to block it. But so far those efforts have failed, and it’s going to take a completely different way of thinking to achieve it.”

Understanding the reasons for this failure explains why targeting MYC is such a Grand Challenge.

Drugging the undruggable

The targets of most ‘smart’ drugs, such as trastuzumab (Herceptin) or vemurafenib (Zelboraf), are usually signalling molecules found on or inside cancer cells. These tend to have a very well-defined shape and structure, with neat biological ‘pockets’ that drugs can be slotted into, like a key fitting into a lock.

MYC is a very different beast. It’s a type of protein known as a transcription factor, responsible for sitting on special stretches of DNA next to genes and switching them on. To do this it needs to be very flexible, buddying up with another factor called MAX (or one of a range of other partner proteins) and moulding into the right shape to nestle into DNA’s double helix wherever it’s needed.

Dr Martin Drysdale, head of the Drug Discovery programme at our Beatson Institute in Glasgow, describes MYC as being “like a disordered strand of spaghetti – it has no defined shape until you attach it to MAX or another partner. And there was always this feeling that targeting transcription factors like MYC was difficult, because people have tried to find things in the past and been singularly unsuccessful.

“It comes down to the complexity of how they work from a biological point of view, but also a lack of information about their shape, and how drugs might interact with them.”

What’s clear after several frustrating years is that our methods of finding cancer drugs – either trying to design a molecule to slot into a pocket in a target, or looking at thousands of different chemicals to find ones that fit – simply aren’t working for MYC.
It’s time for some completely new ideas.


Fresh thinkers needed

“In terms of thinking about the MYC Grand Challenge, what we’re really looking for is innovation in drug discovery,” explains Professor Jones. “People coming together – people who don’t necessarily work on MYC, but who have an interest in drug discovery in general, and thinking about the ways in which we could develop drugs against proteins that are difficult to target in the conventional way.

Prof Nic Jones
Nobody has been able to do this before. If it’s successful, it will be transformational – Professor Nic Jones

“If we get a consortium that comes in and says ‘we’re going to look at a ‘library’ of small chemicals’, well, that’s not going to fly because it’s been done and it doesn’t work. It’s got to be different, and it’s got to be new.”

There are a few interesting approaches that might work. For example, Drysdale is searching for drugs against a similarly ‘undruggable’ target called RAS, looking for tiny fragments of chemicals that stick to it. Could a similar tactic work for MYC?

Biological molecules such as antibodies – highly specific target-hunting molecules generated by immune cells – could be interesting too. As we explain in this post about our new lab in Cambridge, researchers are ‘fishing’ for antibodies that recognise rogue molecules involved in driving cancer, with the hope of finding future cures. So maybe a fishing trip with MYC could be a good idea.

And MYC doesn’t even have to be the main target either. There could be benefits to targeting MYC’s molecular partners or components of the cellular processes and pathways it’s involved in, whether with conventional drugs, antibodies, or entirely new approaches.

What’s more, according to Jones, solving the problem of drugging MYC could reap much wider benefits for cancer patients in the future. “There are good reasons why we’ve chosen MYC, but we hope that we’ll stimulate ideas that could be applicable for other un-drug-able molecules.”

He’s convinced that targeting MYC is a tough but achievable task, making it eminently suitable for a Grand Challenge. “I think the simplicity of it, the clarity of it and the potential to benefit patients in a reasonable timeframe makes it a very attractive challenge.

“Some people might think that because it’s such a specific question it’s not that big. But nobody has been able to do this before.

“If it’s successful, it will be transformational.”

The patient perspective

"I was part of the Edinburgh Big Think and it was a tremendous experience to be involved in finding the questions that need answering. The interaction and coming together of ideas was amazing and it was obvious that many of the researchers from different disciplines had not had previous contact and this was a new way of working. I came away from the event feeling enthused and applied to be part of the patient advisory panel.
Although I have never taken part in a clinical trial, since my diagnosis with breast cancer in 2004 I’ve come to realise the importance that research played in determining the treatment I received. Being involved in the Grand Challenge is my way of giving something back, helping to improve prevention, diagnosis and treatment for others.”
– Margaret, member of the Grand Challenge patient panel
Q7: Grand Challenge seven: kill cancer cells using new ‘smart drugs’

The seventh of our Grand Challenge topics is posing the question: can we kill cancer cells in patients using new ‘smart drugs’?

The Hatton Garden jewel heist of 2015 has been described as “the biggest burglary in English legal history”.

Those responsible successfully entered an underground vault, emptying 72 safety deposit boxes and walking away with £14 million worth of jewels.

But what does gaining access to a vault and emptying safety deposit boxes have to do with cancer? Surprisingly, more than you’d think.

Our final Grand Challenge is the ultimate cellular heist, attempting to sneak the latest ‘smart drugs’ – or macromolecules if we’re being technical – inside the body so they can take out cancer cells.

Big drugs, big potential

Dr Rick Klausner, former Director of the US National Cancer Institute and chair of our Grand Challenge Advisory Panel, describes macromolecules as “machines that have been produced through evolution”.

They are large molecules, pieced together from smaller building blocks. And there are four main types:
  • Nucleic acids – like DNA
  • Proteins – for example antibodies
  • Carbohydrates – things like starch
  • Lipids – things like fats and cholesterol
Each type of macromolecule carries out a wide range of jobs inside cells. They’re essential for growth and survival – without them, cells would die.

And if they become faulty or damaged, things can go wrong.
For example, abnormal build up of the protein Beta-amyloid is found in patients with Alzheimer’s disease, while faults in DNA can lead to cancer.

But macromolecules can also be engineered to help combat diseases. And some have been used as treatments for cancer.

Is bigger better?

Most drugs used to treat cancer patients aren’t macromolecules – they’re much smaller, so they have no trouble getting inside cells.

And if those cells are cancer cells these drugs can do an effective job of killing the tumour cells.

But they have a downside – these drugs can also get inside healthy cells, damaging and killing them as well as cancer cells.

That’s why patients’ hair often falls out when they’re being given chemotherapy treatment. The drugs can’t tell a fast growing cancer cell from a fast growing healthy cell, like a hair cell.

Rick Klausner
We need to develop macromolecule drugs that can get inside cancer cells, where they can do a lot of damage – Dr Rick Klausner

This is one reason why researchers are turning to macromolecules. They know that in some circumstances these molecules have the potential to target and kill only cancer cells.

Some macromolecule drugs – including antibodies like rituximab (Mabthera), which is used to treat Diffuse Large B Cell Lymphoma, and trastuzumab (Herceptin), used for HER2 positive breast cancer patients – have been a great success.

But these treatments have been successful because they don’t need to get inside the cancer cells. They work by targeting and killing cancer cells that have specific molecules on their cell surface.

“These drugs are good, but the problem is they don’t go inside cancer cells,” says Klausner. “They work on the cell surface, messing it up and killing the cell that way.”

So if a researcher wanted to target a faulty molecule inside cells, these macromolecule drugs wouldn’t be up to the job.

If we imagine all cells are like banks – and the cancer cells have their vaults full of faulty molecules we want to target – then the drugs we have work in one of two ways:
  1. Smaller drugs can get inside every bank, and while some will hit a full vault they may also hit some where there’s no cash inside.
  2. Or, we have certain macromolecule drugs – like antibodies – that only work if there’s an ATM built into the bank’s walls that has cash hanging out of it.
“This isn’t enough,” says Klausner. “We need to develop macromolecule drugs that can get inside cancer cells, where they can do a lot of damage.” But why – what’s the advantage of macromolecules that can get inside cells over the drugs and antibodies we already have?

“In the lab we have tools that allow us to develop macromolecules that can correct the fault that’s driving a cancer – by correcting this fault you force the cancer cell to die,” says Klausner.

Essentially, macromolecules have the ability to differentiate between banks with empty vaults and safety deposit boxes and ones containing all the jewels and money.

So far the promise of macromolecules has only been shown in the controlled environment of the lab. What about using these drugs in patients? Will they work in the same way?

Research so far suggests that we can develop and make macromolecules that could be used to kill cancer cells and leave healthy cells alone.

Only there’s one pretty big problem – we can’t get the drugs into any type of cell – cancerous or otherwise – in people.

That’s where our Grand Challenge comes in.

We’re asking the research community to think about how we can get potentially promising ‘smart drugs’ into all the patient’s cells, and not just cancer cells.

“The best bit is that the macromolecule is targeted to only kill a cell that has that specific fault” says Klausner.

“It doesn’t matter if the macromolecule gets into healthy cells as they don’t contain the fault the drug’s designed to fix and would be left unharmed.”

We’re asking researchers to pull off the greatest cell heist ever.


The ultimate cell heist

Before the Hatton Garden thieves carried out their jewel heist they had to be prepared.

They had to bypass the security system and have tools to open the security deposit boxes once inside.

Most importantly, they needed equipment to get through the massive two meter thick concrete walls surrounding the vault.

This is the problem scientists are facing with macromolecules.

They haven’t yet got the tools they need to get macromolecule drugs inside any cell of the body, let alone cancer cells.

“We know an enormous amount about cancer and about the differences between cancer cells and healthy cells,” says Klausner.

“And we have the lab tools to create macromolecules that are designed to fix a specific genetic fault – like a faulty RAS gene or BRCA gene that’s driving a cancer cell’s growth.”

“But they’re no use because we can’t get them into any type of cell – we can’t rob any bank, full or empty.”

“For a long time almost everyone working in this field has been trying to figure out how to only deliver macromolecules to cancer cells. But this Grand Challenge is saying ‘don’t worry about that; don’t worry about being cell specific’. If we can figure out how to get macromolecule inside all cells, the rest will take care of itself – the drug will distinguish a healthy cell from a cancer cell and leave it alone.”

Patient Perspective

In the time since my diagnosis nearly 30 years ago I’ve seen what science can do and the huge advancements it can make. With the technology and knowledge we have now, and with funding schemes like The Grand Challenge, imagine how far we can go in the next 30 years.
This Grand Challenge is about encouraging scientists to think of, and maybe even develop, new ways to get macromolecules into cells in the body. We know it can be done in the lab, but it’s not yet been done outside that environment. If it’s successful, this challenge would take cancer research to another level. It’s a difficult challenge, but I welcome it and the optimism it offers the field of cancer research and cancer patients of the future.
– Terry, member of our Grand Challenge patient panel

Are we there yet?

So how are we going to get there? How are we going to pull off the ultimate heist and get these drugs into cells?

The honest answer is, we don’t know – that’s why this is such a big challenge.

Professor Duncan Graham, a nanoscientist from the University of Strathclyde and an expert adviser to Cancer Research UK, says:  “It’s impossible to predict exactly how this Grand Challenge will be answered. There are techniques available that we could perhaps use to disrupt cell membranes, make them leaky and increase their permeability to bigger drugs. We could use a physical force like ultrasound, or an energy force like localised heating. Or it could be something like low dose, localised radiation or magnetic fields”.
"Answering this Grand Challenge will require bringing together the complementary expertise of different researchers from different areas of science to come up with a radically new proposal and solution to the problem"
– Professor Duncan Graham
“Equally, it could be something completely new and non-traditional. We just don’t know.”

But there is one thing he knows will help us answer the question – collaboration.

“Answering this Grand Challenge will require bringing together the complementary expertise of different researchers from different areas of science to come up with a radically new proposal and solution to the problem,” says Graham.

“Every time I speak to cancer researchers I find out a bit more about cancer. And they find out a bit more about nanoparticles – the science behind them and how they could be useful to them. It’s not an area they’re aware of because it’s such a different field from theirs.”

Klausner agrees: “This problem is going to be solved by bringing together people who understand biology, physiology and cells with chemists, material scientists and people in the imaging field. We need to bring together people from very different areas to achieve this.”

There is one thing we can be sure of though.

If we overcome this Grand Challenge and work out a way to get macromolecules into cells, there is massive potential for offering new treatment options to patients.

That’s definitely something to aim for.

Virtual reality and precision diagnosis among shortlist for our Grand Challenge

Giving scientists the freedom to think outside the box is important. But it also raises an interesting challenge around how to prioritise big ideas.

On the one hand, voyaging into the unknown to study the fundamentals of biology can yield unimaginable results. And giving scientists free rein to explore ideas has been at the heart of much scientific progress.

But other forms of research – for example, the meticulous and methodical design of clinical trials, or systematic analysis of ‘big data’, are also vital in helping develop the latest cancer treatments.

As an organisation that funds research on almost every aspect of cancer, balancing where the money goes across these different areas of research is no mean feat.

And it’s one reason why we divide our research focuses up into different areas – with each of our many funding schemes carefully managed and assessed.

But just over a year ago, we announced plans to do something completely new: the Cancer Research UK Grand Challenge.

It’s a £100 million scheme spanning the next five years that aims to tackle the biggest questions in cancer prevention, diagnosis and treatment. And it makes it all the more important to align the ‘hottest’ ideas with those that have the greatest potential impact.

It’s clearly caught the imagination of the global research community: in the five months since we opened the scheme 57 teams, comprising scientists from 25 different countries, have made an initial application for funding – proposing a whole host of possible ways to answer the questions.

And now, our expert panel has picked nine of them to go through to the next stage. Over the next few months they’ll hone these initial ideas, before a final decision is made on who will get the money.

And as we’ll explore below, these nine teams have already produced some potentially revolutionary new ideas.

A vaccine to prevent cancer

One of our Grand Challenges was to develop a vaccine to prevent cancers developing – and one team has proposed a potentially ingenious way to solve it. Growing tumours crave a nourishing blood supply carrying nutrients and oxygen. The team proposes to develop a vaccine that could cut this supply line off .

Professor Roy Bicknell, from the University of Birmingham, and his team of of experts from five countries, has already identified molecules that encourage blood vessels to grow. And these are also found at high levels within certain tumours, where they may be among the first signals that cause tumour blood vessels to form.

The team is proposing to develop a vaccine that would alert the immune system if the body begins to make these molecules, and thus prevent cancer cells from calling out for a new blood supply. If they can work out how to target the right molecules in the right healthy people, the vaccine could cut off a tumour’s life support before it has chance to start growing.

Taking down a virus

Vaccines also featured as part of the second shortlisted application, aiming to tackle our second Grand Challenge: to eradicate cancers caused by the Epstein-Barr Virus (EBV).

Professor Alan Rickinson, from the University of Birmingham, has drawn together some of the world’s leading experts in EBV research from eight different countries. And they are proposing a two-pronged attack on the virus, which causes around 200,000 cases of cancer around the world each year.

Building on previous lab research, the first line of attack is to develop new treatments for cancers caused by the virus, and test these in clinical trials. The second, simultaneous, route of attack would involve studying in unprecedented detail how the virus affects molecules and processes inside infected cells.

They hope that pooling all the information learnt from these studies, and combining it with work to understand exactly how the immune system recognises EBV infection, will ultimately lead to a vaccine to prevent cancers caused by the virus, bringing with it the potential to prevent hundreds of thousands of cancer deaths.

What causes cancer?

Knowing how to prevent cancer relies heavily on understanding the processes that trigger it.

And researchers now know that these processes – whether environmental, lifestyle-based or genetic – leave a telltale pattern of damage within a cell’s DNA. Researchers have so far pinpointed 30 of these ‘mutational signatures’ in human tumours, but only half are linked to a known cause.

The third shortlisted team, led by Professor Mike Stratton from the UK’s Wellcome Trust Sanger Institute, including experts from three countries, aims to solve our third Grand Challenge – preventing cancers by pinpointing their causes.

During the shortlisting, one of the members of our Grand Challenge scientific panel – Professor Tyler Jacks, director of the Koch Institute in the US – described this approach as “grand in that it approaches many different types of cancer”. And Stratton’s team hopes they will be able to link more of these signatures to the processes that cause them.

They then plan to apply this to how the rates of different types of cancer vary around the world, piecing together where the impact of different causes is felt most.

The overall goal of this research would be to find ways of monitoring the appearance of these signatures in healthy people, thus opening up new ways to prevent the disease.

Better diagnosis

Spot the difference.
Finding a way for doctors to spot the difference between potentially lethal tumors that need treating, and those that won’t cause a patient any harm, isn’t easy. But it’s the goal of our fourth challenge. And our panel shortlisted three teams hoping to take this on, all with a slightly different approach, and each focusing on a different type of cancer.

Led by the University of Oxford’s Professor Freddie Hamdy, and including researchers from three different countries, one team plans to focus on prostate cancer, throwing the latest DNA analysis and imaging technologies at thousands of tumour samples. They hope to find a unique ‘signature’ for both lethal and non-lethal tumours hidden in these data, which they then plan to test in a large clinical trial.

The next shortlisted team, led by the University of Southampton’s Dr Surinder Sahota, including experts from four different countries, is searching for a way to accurately predict whether patients with a pre-cancerous condition called monoclonal gammopathy of undetermined significance (MGUS) will go on to develop multiple myeloma, a cancer that starts in the bone marrow.

The team proposes to scour the DNA of people with MGUS in search of changes that are also found in myeloma. Combining this with information about faulty molecules inside cells and how the immune system reacts to myeloma, the team hopes to be able to predict, as early as possible, who will develop cancer.

The third shortlisted application for this challenge came from an international team led by Netherlands Cancer Institute’s Dr Jelle Wesseling. And according to another of our panel members, Professor Sir David Lane, Scientific Director of the Ludwig Institute for Cancer Research, Chief Scientist at Singapore’s Agency for Science, Technology and Research (A*STAR), it gets at a “critical clinical question” – working out a way of predicting whether cells that have started to become cancerous in the breast – so called ductal carcinoma in situ (DCIS) – will go on to become invasive breast cancer.

DCIS poses a real problem for doctors. It’s not yet possible to predict which patients will go on to develop dangerous breast cancers that need treatment, and which won’t.

By studying large collections of data from clinical trials in the UK, Europe and US, Wesseling’s team aims to solve this crucial problem, giving doctors an urgently-needed way of telling the difference between these cancers.

Virtual reality

Map data visualisation
Credit: /CC BY-SA 2.0

Three applications were shortlisted to solve our Challenge of developing a ‘Google Street View’ for cancer. Solving this, said panel member Professor Suzanne Cory, from the Molecular Genetics of Cancer Division at The Walter and Eliza Hall Institute in Australia, could “move us into a different future”.

And with virtual reality in the mix it’s easy to see why.

The first team, led by Cambridge’s Professor Greg Hannon, and including scientists from five different countries, plans to focus on breast cancer. Combining technology that can track the movement and fate of cells in living tissue with molecular and genetic information, the team hopes to build a virtual reality experience that will allow researchers to ‘walk around’ inside 3D virtual tumours.

Breast cancers can be categorised into 10 distinct ‘types’ and the team plans to map each of these different diseases, along with clinical information about how patients with each type fared. This could open up an entirely new way for scientists and doctors to view how tumours develop and respond to treatment.

The second shortlisted application in this area is led by Professor Ehud Shapiro, from the Weizmann Institute in Israel, and once again featured an exciting proposal involving virtual reality.

Not content with mapping tumours in three dimensions, Shapiro’s team, made up of scientists from three different countries, plans to add a fourth: time.

Using the latest technology, they hope to track patients from diagnosis through treatment and even, in some cases, after death. In their application the team said that trying to look at the huge volumes of data that might result wouldn’t be “directly comprehensible”. So they’ll need to develop cutting edge new software to turn this complex data into a new, virtual reality.

Ultimately, they hope to produce the most comprehensive view of a tumour, stretching from its earliest origins to when it begins to spread and beyond. And they want to do this for every patient, with the hope of finding the best way to treat people in the future.

The third team, led by Dr Josephine Bunch from the National Physical Laboratory, propose combining three cutting-edge areas of research – machinery called mass spectrometry that can measure all the molecules inside individual cancer cells; the latest imaging technology; and next-generation genetic analysis – to generate detailed ‘molecular maps’ of tumours.

Combining the team’s expertise from several different scientific disciplines, they hope these maps will offer ways to group patients to help test personalised treatments, as well as finding new ways to accurately diagnose and monitor tumours.

What happens next?

We’ll now be supporting each team to further develop their approach, and submit a full application. Our expert panel will then meet again later this year to decide where the money will go.

On the subject of where this decision may end up, Professor Nic Jones, director of the Manchester Cancer Research Centre and member of our Grand Challenge scientific panel was quite clear during the shortlisting: “There’s no point doing exciting science if it’s not going to be transformational.”

And it would seem that, among these proposals, there are the teams and the ideas that have the potential to do both.

3 of the toughest questions in cancer and more than £70 million to solve them

There was excitement in the air as 10 of the world’s leading scientists deliberated on their decision. After months of hard work and sleepless nights, they were selecting the first winners of our Grand Challenge awards.

“We were almost pinching ourselves when we read the winning teams’ applications”, explains Dr Rick Klausner, chair of the Grand Challenge Advisory Board.

“They were among the most exciting I’ve ever read, and I’ve been reading and reviewing funding applications for almost 40 years!”
Originally, the plan was to fund 1 team. But the quality of the shortlisted teams led the panel to recommend we fund 4, which we’re announcing today.

Together, they will receive more than £70 million over the next 5 years as they attempt to answer 3 of the toughest questions on how to prevent, diagnose and treat cancer.

According to Klausner, one of the reasons these teams stood out was their willingness to work together, combining the expertise of scientists from different disciplines in each team.

“We’re now at a point in cancer research where we realise that to solve the remaining problems, scientists from different disciplines have to come together,” he says.

“Chemists, biologists, physicists, computer programmers, data analysers, people working in labs and people in the clinic must all join forces.

“Other funding schemes recognise this, and encourage scientists to collaborate. But the Grand Challenge is unique in that it doesn’t just encourage scientists to form such alliances, it requires them to.

“These 4 winning teams have more than met that requirement. They have brought together experts from around the world, and from different scientific disciplines, to solve some of the biggest problems we face in cancer research.

“Problems that if solved, will dramatically change our approach to the disease, and our ability to study, prevent, diagnose and treat it.”

Years in the making

These awards are like nothing we’ve ever funded before. So getting it right has been a long journey.

Here’s how we reached today’s decision:

The winning teams

Over the coming months we’ll be taking an in-depth look at the 4 winning teams’ research. But for now, here’s a brief overview of what they plan to do with their Grand Challenge funding.

Dr Josephine Bunch – Develop a ‘Google Earth’ for tumours to improve cancer diagnosis and treatment

Dr Josephine Bunch
Dr Josephine Bunch

In the same way cartographers make maps of cities, countries and the world to help people get around, scientists use microscopes, gene-sequencing technology and a host of other techniques to build maps of tumours. The goal is to better understand the inner workings of tumours, in the hope this will lead to new ways to diagnose and treat cancer.

But despite significant advances in technology and our understanding of cancer, our tumour maps remain incomplete.

Through their Grand Challenge project, Dr Josephine Bunch, from the National Physical Laboratory in London and her team of UK and US-based scientists, want to change this. Using their expertise they aim to find a way to fully map different tumours in unprecedented detail. And they aim to ensure that all labs and hospitals around the world will be able to use their technology to do the same.

The team will do this using specialised new technology called mass spectrometry imaging, which measures all the molecules inside tissues and cells to build a complete picture of that tumour.

Amazingly, Bunch’s team, which includes the inventors of many of the machines they’ll use in their work, are the first in the world to combine all these technologies.

And they will map every detail of a series of tumours, zooming in from the whole tumour right down to the individual fats and molecules inside cells (metabolites), as well as studying the cells and molecules around the tumour.

They hope that by creating such detailed pictures of the ‘beating heart’ of these tumours they will improve our understanding of all cancers, leading to new and better ways to diagnose and treat them.

To begin with the team will study individual breast, bowel, pancreatic and brain tumours. They chose these cancers because they want to show that their new technology can be used to map different tumours from different parts of the body that each hold their own unique challenges.

But perhaps, more importantly, this selection is based where the team believe their work could make the biggest difference to patients, fastest.

Professor Sir Mike Stratton – Discovering the causes of cancer by studying DNA ‘fingerprints’

Professor Sir Mike Stratton
Professor Sir Mike Stratton

The environment we’re exposed to and some of the things we choose to do, like smoking and drinking alcohol, can increase our risk of cancer by damaging our cells’ DNA. This damage occurs in distinctive patterns – known as mutational ‘fingerprints’ – which are unique to the cause of that damage.

Right now, scientists have found around 50 of these ‘fingerprints’ that are linked to cancer. But they only know what causes around half of them.

Professor Sir Mike Stratton from the Wellcome Trust Sanger Institute in Cambridge, and his team of scientists from the UK, France and the US, together with collaborators from the International Agency for Research on Cancer (IARC), want to fill in the missing gaps.

Their Grand Challenge project aims to work backwards from those ‘fingerprints’ with an unknown cause to reveal the biology behind them. And ultimately find out what caused them.
It’s a project on an epic scale that spans 5 continents.

The team will study the ‘fingerprints’ in 5,000 pancreatic, kidney, oesophageal and bowel cancer samples, which come from countries that have different levels of these cancers.

They’ll also collect information about the habits, lifestyles and environments of the people from whom the samples originate, searching for clues to what the causes might be, and why some cancers are more common in some parts of the world than others.

This research could dramatically improve our understanding of what causes certain cancers and lead to better information for people on how to reduce their risk of developing these diseases.

Professor Greg Hannon – Using computerised 3D tumours and virtual reality to better understand cancer

Professor Greg Hannon
Professor Greg Hannon

To fully understand cancer, scientists need to know everything about a tumour – what types of cells are in it, how many there are and where they are located in the tumour.

But getting such a precise picture of tumours is extremely difficult to do. So difficult that it’s not been done before.

Professor Greg Hannon, based at our Cambridge Institute, and his team of scientists, computer experts and virtual reality developers from the UK, Canada, Switzerland, the US and Ireland want to change this.

Their Grand Challenge project, which will attempt to tackle the same challenge as Bunch’s team, aims to build computerised 3D tumours from real samples that can be studied using virtual reality and show every single different type of cell in the tumour.

Starting with breast cancer, they aim to gather thousands of bits of information about every cell – from cancer cells to immune cells – to find out which cells are neighbours, how they interact with each other, and how they all work together to help tumours survive and grow.

This will involve building specialised microscopes from scratch, as well as collecting genetic data for each of the millions of cells that can be found inside a tumour.

They will then take the vast amounts of data they collect and use this information to build a computerised 3D version that can be studied using virtual reality, allowing scientists to immerse themselves in a tumour and study patterns within it that can’t be seen by simply looking down a microscope or at charts of gene data.

By developing this entirely new way to study cancer, this team hopes to change how cancer is diagnosed, treated and managed.

Dr Jelle Wesseling – Finding ways to spare women unnecessary treatment

Dr Jelle Wesseling
Dr Jelle Wesseling

Ductal carcinoma in situ (DCIS) is a condition that sometimes develops into breast cancer.

But right now, doctors can’t tell whether women with DCIS will go on to develop breast cancer or not. This means that, unfortunately, some women with DCIS undergo hospital visits, surgery and even chemotherapy and radiotherapy that they don’t need.

Through their Grand Challenge project, Dr Jelle Wesseling, based at the Netherlands Cancer Institute, and his team of scientists from the UK, the Netherlands and the US want to change this, and stop women getting unnecessary treatment.

To achieve this, Wesseling’s team will study tissue samples taken from women with DCIS during surgery. They will look at these samples in great detail and gather clinical information about these women, recording whether their DCIS came back, if they later developed breast cancer, and if so, whether it spread.

The team will then combine all of this information to search for clues in the DNA of women who had DCIS to see if they can predict how likely they were to develop breast cancer later on.

By finding ways to distinguish women with DCIS who have a low or high risk of developing cancer, this project has the potential to spare thousands of women unnecessary treatment, while making sure those who need it, get it.

The future looks bright

Together, these 4 teams want to bring about a revolution in how we think about, prevent, diagnose and treat cancer. And it’s an ambition on a global scale.

“Cancer is a complex and often brutal disease,” says Klausner.

“Cancer Research UK’s Grand Challenge awards are helping us change the way we tackle it – bringing together different disciplines, ideas, and people on a global scale.

“These unique teams have done that in a truly remarkable way. I can’t wait to see what their research brings and the impact it will have around the world.”

‘Google Earth’ for tumours could change cancer diagnostics and drug testing forever

Think of a tumour like a rapidly growing city within a patient’s body.

Doctors can scan the patient to locate the tumour, much like a satellite can scan the earth and map its cities. And scientists can get a sense of the tumour at ‘street level’ by looking at its communities of cells through tissue samples and gene-sequencing technology.
But combining all this information for each cell in a tumour to guide diagnosis and treatment can’t yet be done.

Our ability to navigate this city, and how it changes, is incomplete. And no single scientific technique can capture all the details of a tumour to recreate zooming in and out of a map on a smartphone, for example.

Without more complete maps of tumours, scientists and doctors are wandering through unknown territory.

“Until we completely understand how tumours are made up it will be very difficult to develop the next wave of treatments for cancer,” says Dr Josephine Bunch, from the National Physical Laboratory (NPL) in London.

But Bunch’s international team, which received £16 million through our Grand Challenge award last month, think they now have the technology to make complete maps of tumours that are so desperately needed.

This is the place to make measurements

Her team will attempt to map every detail of several types of cancer, cataloguing the intact tumour tissue right down to single cells and the molecules held within them. And they’ll focus on the processes that fuel how tumours grow (metabolism) with the goal of improving diagnosis and treatment.

Dr Josephine Bunch
We wouldn’t have responded if we didn’t have huge confidence in our approachDr Josephine Bunch

It’s like stitching together a ‘Google Earth’ for tumours, she says.

And according to Bunch, there’s no better place to be taking on this challenge than NPL, which is the UK’s national measurement institute.

Its teams hold the UK kilogram, set time across the country and calibrate all the radiotherapy machines in the NHS.

Making reproducible measurements is what they do, says Bunch. And that will be the focus of their Grand Challenge project as they attempt to create tumour maps that can be reproduced by any scientific or medical team anywhere in the world.

According to Bunch the team was “under no illusion” that what it’s proposing would be easy. This is because the team has been tasked with measuring some things that are relatively big (an entire tumour) right down to some things that are very small (individual molecules inside single cells), as quickly as possible. “But we wouldn’t have responded if we didn’t have huge confidence in our approach,” she adds.

When you think of mapping something the most obvious method that springs to mind is taking a picture of it. And in science you might think this means microscopes and scans.

Bunch thinks differently.

“If you look down a microscope then you’re most often looking at the structural composition of that tissue,” she explains.

Classically this involves using a chemical stain to light up cells and molecules you’ve chosen to look for. And while that’s useful in many ways, Bunch says this falls short in two areas.

First, just looking at the overall structure and shape of a tumour can only tell you so much about the different types of cell the tumour holds, and how they interact. Second, using a chemical stain means “you have to know what you were looking for,” because these stains show up “a particular protein and you’re looking where that is.”

The challenge isn’t in measuring what scientists know to look for. “If we knew what to look for we’d have found it already,” says Bunch. Instead, they need to measure everything, and hunt through these data for patterns. Bunch’s team plan to do this by measuring the chemical and molecular details of tumours in an unbiased way, as comprehensively as possible.

And they’re doing this by combining a series of techniques that have never been used together before.

A chemical ‘snapshot’

The team’s labs at NPL span workshops where they’re developing everything from new lasers through to a machine that’s the only one in existence in the world.

Each of these specialised instruments is built around a measurement technique known as mass spectrometry, which detects molecules based on their unique mass.

It dates back to the beginning of the 20th century, but in the last few decades a series of new instruments has been developed that uses mass spectrometry data to build a picture of the sample that’s being analysed.

“What we do is measure as many molecules as we can at one location,” says Bunch. The instrument then moves its focus a fraction further along the sample and makes the same measurement again.

“We do this at hundreds of thousands of locations across the sample so we end up with an enormous amount of data that we can mine in different ways,” she adds. From these data we can identify molecules and show where they are in the sample. And this is all without being biased in hunting out a particular type of molecule or cell that the scientist has chosen to look for.

The problem with mass spectrometry, Bunch explains, is that the different ways the instruments work mean that you can only measure certain properties of your sample in each experiment. It’s like trying to find a place to eat using a map on your smartphone, but needing to switch to a different device to see each different type of restaurant.

This means that with one machine you might be able to measure something relatively big, a complete piece of tumour tissue for example. But you need another machine to get reliable information about small things in that sample, such as molecules inside single cells in the tissue.

And that’s why Bunch’s team, which includes many of the inventors of the technology they’ll be using, has proposed bringing several instruments together to map tumours in never-before-seen detail.
The techniques range from an advanced surgical knife (called iknife) that can distinguish between healthy and cancerous tissue during surgery, to instruments that can spot individual molecules and drugs inside cells.

And the team is kicking off the project by looking at bowel, breast and pancreatic tumour samples from mice and patients.

Starting with 3 types of cancer

They chose these cancers because they each “present a very different challenge in measurement,” says Bunch. That’s because each of these types of tissue “are actually very different” so testing their technology against these cancers will make sure it can be applied to as many types of cancer as possible in the future.

By zooming in and out of these tumours the team will be able to pick out key characteristics of these cancers. They’ll also be mapping this against how certain drugs work, sharing the data with their pharmaceutical partner AstraZeneca to help speed up how the findings might lead to new treatments.

Grand Challenge
The team plans to zoom in using different instruments to inspect important areas of the tumour. Credit: Zoltan Takats, Renata Filipe-Soares (Imperial College London); Nicole Strittmatter, Gregory Hamm, Richard Goodwin (Astra Zeneca); Rory Steven, Adam Taylor, Alan Race, Spencer Thomas, Rasmus Havelund, Josephine Bunch (NPL).

They also have their sights set on how these instruments might be used in a clinical setting, both in pathology labs and for monitoring treatment.

“We envisage mass spectrometry imaging being used more fully in a clinical setting,” says Bunch. “We hope to show how we can make measurements that will be superior to traditional ways of doing things.”

One way they’ll do this is with the iKnife, which will gather vital information about these cancers in patients during surgery.
But they plan to take this a step further.

“It would be nice if a patient didn’t have to undergo surgery for those measurements to be taken,” she says.

So they will be studying their maps to see how they match up with advanced MRI scans through a collaboration with Professor Kevin Brindle from our Cambridge Institute.

By aligning their data with Brindle’s, Bunch hopes to develop the least invasive way of understanding the aggressiveness of a tumour and monitoring if treatment is working.

But then comes the challenge of data.

Creating 1 image with 1 technique will produce around 100 gigabytes of data, Bunch estimates.

“We’re going to collect hundreds and hundreds of these images using the multiple techniques over 5 years. So a huge challenge of this project is curating, mining and sharing those really precious data.”

And the team is already hard at work finding ways to handle this.

Once their database is complete, the next step will be to focus on the measurements and areas of the map that carry the most important information about the tumour.

“The idea is that we might find things that you could then look at in a slightly more targeted manner,” says Bunch.

It’s these more focused observations that could uncover new targets for drugs, or characteristics of tumours that may lead to new tests or scans.

A measurement that anyone can make

Behind the technical ambition of this project sits Bunch’s desire to make sure the team’s measurements can be made by others too.

That’s the only way this will help improve the outlook for patients, she says.

“It’s very important to us that this kind of work, and particularly this investment, delivers methods that are reliable and can be used by other laboratories.

“We will be producing a large searchable database of our ‘Google Earth’ view of tumours, which will be freely available to researchers around the world.

“We don’t want to be the only people who have the knowhow to make these measurements.”

Making a difference for patients

There’s a long and difficult journey ahead. But Bunch has her heart set on the difference their tumour mapping could make for patients.

“We want to find new ways of diagnosing cancers, we want to develop new treatments and we want to have a major impact on patients’ experience from when they are first diagnosed all the way through their treatment.”

A big part of making this happen will come through involving patients and the public in the design and assessment of the ongoing research.
"They are very inclusive and open to learning new things and doing things in different ways while being focused on the task at hand"
– Kelly Gleason, research nurse
Kelly Gleason, a research nurse from Imperial College London, and Harry Hall, who was diagnosed with bowel cancer in 2002, will be guiding the Bunch team along the way.

The team sees the purpose and benefit of involving patients in their research, says Kelly. “They really want to get this part right.”

“This is a very exciting time for scientists, but also patients and anyone touched by cancer… it brings such hope,” she says.

Kelly and Harry have been a part of the Bunch team from day one. “Josephine and her group have prepared us to be included at every meeting,” says Kelly. And Kelly will be welcoming the team to her patient and public involvement group at Imperial to discuss the next steps for involving patients in the project.

“I feel very confident this team will deliver what they have promised,” says Kelly. “They are very inclusive and open to learning new things and doing things in different ways while being focused on the task at hand.”

This is something that Bunch makes very clear.

“We need drugs to be more effective,” she says. And for that to happen “you have to understand the molecular basis of the disease you’re treating.”

More accurate diagnostics could follow too, with “less invasive measurements and answers faster.”

It’s not yet clear what the team will uncover. “If we knew what we needed to measure we’d have already done it.”

But they’re confident that a ‘Google Earth’ for tumours will help guide the way.


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