Abstract
In order to speed progress in cancer research, it is necessary to recruit the best scientists, irrespective of discipline or geographical location, to tackle the barriers that still lie ahead. Cancer Research UK's recently launched £100m Grand Challenge grants scheme is specifically designed to facilitate collaboration between the physical and biological sciences. We are seeking multidisciplinary, international teams of scientists to come up with innovative, ambitious proposals to solve seven of the toughest challenges left in cancer research. The scheme is intended to catalyse the formation of a global Grand Challenge community, and to reward hypothesis-driven, blue-skies thinking.
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The 21st century story of cancer is far more positive than it has ever been before: prevention, screening, and improved survival with the more treatable cancer types have saved millions of lives. Today, 2 in 4 people in the UK are surviving cancer for more than ten years, and many experts believe that this figure will rise to 3 in 4 within the next two decades (Achieving World Class Cancer Outcomes: A Strategy for England 2015–20203). However, there is still a dark side to the plot. Despite a revolution in what we know about the basic biology of cancer, there are still primary cancers where a cure remains an aspiration rather than a reality, and the prognosis for someone with metastatic cancer is almost as grim today as it was 50 years ago [1]. We have established some significant bridgeheads into formerly hostile territory, but we have not yet won the war against cancer; when the Nobel laureate and cancer geneticist Harold Varmus became director of the US National Cancer Institute in 2010, he told an audience: 'We have not succeeded in controlling cancer as a human disease'.
A cancer Grand Challenge
How can we capitalise on our advanced understanding of cancer at a biological level, and on the development of increasingly sophisticated technologies, to expedite progress? This autumn, to encourage more ambitious, innovative research on the biggest problems in cancer, we at Cancer Research UK, the world's largest cancer charity, launched the Grand Challenge awards. Over the next five years, a total of five grants, of up to £20 million each, will be made to multinational, interdisciplinary teams proposing to tackle major barriers holding up progress towards controlling or curing cancer.
Cancer Research UK's decision to pioneer what will be the biggest research grants in the cancer field was motivated by several factors. In recent years, there has been an increasing trend towards safety rather than innovation in cancer funding; with the increasing pressures within the academic system, including on funding, large programme awards tend to be made to established names in established fields, and whilst this is a reasonable guarantee of progress, it does not necessarily encourage provocative thinking, or interdisciplinary collaboration at the margins of fields [2]. This conservative approach could not have come at a worse time: the more we learn about cancer, the more we learn that, far from the reductionist ideal of the earliest molecular biologists, the complexity of cancer is almost overwhelming. Unfortunately, the approaches necessitated by this complexity have been suggested by many to be stifling traditional scientific thought—'the coupling between observational data and biological insight is frayed if not broken' [3]—and cancer biology is still struggling to recruit incomers from other fields, whose insights will inevitably aid progress.
Cancer Research UK's aim with the Grand Challenge awards is to overcome this fiscal and intellectual conservatism, and to complement this by mobilising the international scientific community. We are committed to supporting bold, innovative ideas, and to working closely with winning teams to facilitate their research. Perhaps most importantly, the large-scale nature of the funding will free investigators from some of their other more mundane tasks, allowing them to rediscover the freedom to think, uninterrupted, about really big problems. Ultimately, the ambition is to establish an interdisciplinary global community of scientists, and to develop a funding model, perhaps by partnering with other foundations and institutions, that is able to respond intelligently and flexibly to new challenges in cancer.
The first cancer Grand Challenges have been decided after extensive discussion with the scientific community. Consultation sessions, where participants were encouraged to think well beyond the limits of their own research priorities, gave scientists from many disciplines, including some not normally associated with cancer biology, the opportunity to stretch their intellectual curiosity and decide what barriers were truly constraining entire fields. These barriers, and other major problems in cancer, were considered in September 2015 by the Grand Challenge Advisory Panel4. In deciding which Challenges should be set, the panel recognised that there were clearly remaining barriers; the intention is to continue the debate with the science community to add or amend Challenges as the scheme evolves.
The seven initial Grand Challenges are not focused on immediate clinical benefit; their aim is to tackle the roots of problems, and stimulate entirely new ways of thinking in the process. Their scope reflects a balance between breadth and specificity, and between ambition and possibility—the panel deliberately chose a set of challenges that in some cases were very specific, but required new approaches, but in others were quite broad, encompassing a number of barriers that need to be overcome. As has happened with the Bill and Melinda Gates Foundation's Grand Challenges5, the hope is that the existence of each Challenge will generate interest in previously neglected or complex areas, spawning high quality work from many laboratories [4].
How might the physical sciences participate in these potentially game-changing Challenges? Broadly speaking, there are three possibilities. The 'biologist with problem meets physicist with technique' method is an old and well-established mode of interaction, and has led to huge advances, notably in medical imaging. Physicists, mathematicians and computer scientists have also made enormous contributions to meeting the bioinformatics data challenge posed by modern biological methods. However, whilst this type of collaboration will undoubtedly figure in Grand Challenge applications, what we also seek to promote are more equal partnerships, where physical scientists work in close contact with biologists, with each side bringing their own viewpoint and expertise to focus on a fundamental cancer problem.
This latter mode of thinking is comprehensively discussed in the APHELION6 study, published in late 2013, which summarised how physical sciences and engineering principles might be applied to cancer research. More recently, Risler [5] has updated the questions and problems being tackled by physicists in the cancer research field, breaking them into seven distinct categories. All feature in potential diagnostic and therapeutic strategies; simply put, we need to consider the physical properties of cancer cells as well as their molecular characteristics when trying to distinguish them from normal tissues, when trying to kill them, and when trying to detect them.
Grand Challenge is an opportunity for the global physical and life science communities to co-create a new and exciting way of thinking. Now is the time to dust off your brilliant, more ambitious ideas from the back of your shelf, and fire them up again, as you finally have a place where they will be looked at favourably. Read the Challenges, and think seriously about how you might assemble a team to apply: we will be delighted to hear from you.
The seven Grand Challenges
Challenge 1: to develop vaccines to prevent nonviral cancers
Vaccines already exist that prevent cancers caused by infection, such as against the human papilloma virus that causes some cervical cancers. But this challenge is to develop vaccines that work against non-viral cancers, which are caused by faults in our DNA that accumulate over time. However, because cancer is a disease of the body's own cells, it is more challenging to coax the immune system to recognise and eliminate early stage cancers, where the difference between healthy cells and abnormal cells might be very small. But the promise is huge: if we could vaccinate against cancer as we do for infectious diseases such as TB and measles, could cancer disappear?
Challenge 2: to eradicate EBV-induced cancers from the world
Around 19 in 20 adults carry the Epstein Barr Virus (EBV), making it one of the most common human viral infections. In most people, EBV is relatively harmless, although it's the cause of glandular fever, 'kissing disease'. But in some parts of the world it's a big problem—every year, EBV infection accounts for 200 000 new cases of cancer worldwide, and more than 140 000 deaths.
Whilst this is partly a vaccine challenge, there is also scope to develop drugs that target EBV-infected cells. Both require significant technological advances, particularly in terms of vaccine development. Given that EBV-induced cancer is a particular problem in the less developed world, any effective vaccine or drug would need to be heat-stable and cheap.
Challenge 3: to discover how unusual patterns of mutation are induced by different cancer-causing events
We know that unexpected patterns of mutation in DNA can be used as flags to identify exposure to previously unknown carcinogenic agents. This Grand Challenge seeks to expand this concept and to explore whether a unique signature of DNA mutation, or any previously unrecognised but characteristic pattern of tumour alteration can be used to identify novel tumourigenic events. This reversal of the standard flow of epidemiological experimentation—starting studies with an unusual but characteristic pattern of change found within a tumour or its DNA rather than beginning with unusual patterns of cancer incidence—could be used to find novel types of tumourigenic insult—the DNA-damaging processes or chemicals behind cancer.
Ultimately this challenge would allow us to understand the mechanisms that lead from insult to mutation, identifying new prevention targets to stop, delay, or weaken their impact. And by studying the proportion of the population with these signatures, we might also find individual variations in DNA repair or immune response that identify people at higher risk who would benefit from more targeted intervention.
Challenge 4: to distinguish between lethal cancers that need treating, and non-lethal cancers that don't
Our current early detection strategies suffer from over-diagnosis leading to over-treatment (breast and prostate cancer) or from the inability to detect cancers at an early stage leading to a high cancer-specific mortality (pancreas, lung, ovary). The premise of this challenge is that we need a thorough understanding of features, both biological and physical, that distinguish a non-lethal growth from a lethal malignancy, to enable methods to be developed that specifically detect malignancies that require intervention versus growths that can be safely monitored. There are two aspects to this challenge: identifying changes that distinguish a non-lethal from a potentially lethal tumour, and then determining how these changes could be detected accurately.
Challenge 5: to find a way of mapping tumours at the molecular and cellular level
A tumour is a complex and organised organ comprising many different cell types. Although we know that different populations of cells are present within a tumour, the most common method of analysis, in which the tumour is pulled apart and cells are studied separately, gives us little or no information about why cells are there, how they got there, and what they are doing. This Grand Challenge seeks to overcome this barrier by taking a holistic view of tumours as an integrated, organised population of cells, rather than a reductionist approach studying very small parts of the problem. Technologies are just now emerging that would allow 3D mapping of the cellular and molecular details of primary tumours and metastases. The ability to create detailed maps of the mutational heterogeneity, full RNA expression and protein expression, all at the single cell level and across all the cells and cell types could open up a 21st century approach to defining and even classifying tumours. Such an achievement could provide the basis for a dynamic view of a tumour over time and in response to treatment, and might give us the potential to target and eliminate the most dangerous 'cancer hotspots' in tumours.
Challenge 6: to develop innovative approaches to target the cancer supercontroller MYC
The MYC oncogene contributes to the genesis of many human cancers, and tumours with elevated MYC often exhibit highly proliferative, aggressive phenotypes. Experimental models have convincingly shown that MYC is required for tumour maintenance. These studies strongly predict that inhibiting MYC will have a profound effect on tumour survival and provide a significant new approach to treating many human cancers. All attempts to inhibit MYC have failed, and therefore it represents a clear and significant barrier to curing cancer.
Challenge 7: deliver biologically active macromolecules to any and all cells in the body
Over the past several years, scientists have learned how to deliver macromolecules into tumour cells in the laboratory that effectively and selectively kill any tumour cell, based upon its unique molecular profile. If the same macromolecules (protein, DNA, RNA, siRNA, CRISPR, antibodies, etc) could be delivered in vivo to any cell in the body, it would create a totally new and effective approach to treat cancer, essentially applying the exquisite specificity of macromolecules to replace traditional small molecule drugs.
The focus of this challenge is on delivery mechanisms: designing macromolecules so that they can be taken up by a cell's normal import mechanisms. This is an extraordinarily large challenge, as there are many unresolved components of the delivery problem. These include: establishing the optimal delivery method; crossing endothelial and interstitial barriers (including the blood–brain barrier); pharmacokinetic issues, and a deepened understanding of cell membrane transport mechanisms. Progress in any or all of these areas will take us closer to overcoming the most important barrier to efficient drug delivery.
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