Overcoming the evolution of cancer

Deformed cells in the bone marrow, typical of chronic leukaemia (photo: Difu Wu/CC BY-SA 3.0)

Evolution is the central idea of biology – a concept that helps shape our understanding of the origins of life, and of the way living things behave and interact.

So perhaps it’s not surprising that evolution has come to be seen as one of the most important concepts, and greatest challenges, in cancer research. It’s now a problem that The Institute of Cancer Research, London, is confronting head on.

Cancer kills more than 160,000 people in the UK every year¹, and in most of these cases what proves lethal is cancer’s ability to develop resistance to treatment, and to spread around the body.

In recent years, it has become clear that underlying the development of resistance is an evolutionary process – a kind of ‘survival of the nastiest’, where those cancer cells that are most aggressive, and least responsive to treatment, are most likely to survive and thrive.

In July 2016, experts at the ICR and The Royal Marsden NHS Foundation Trust set out a roadmap to combat cancer, specifically by tackling its propensity to adapt and evolve.

The first pillar of this research strategy is all about gaining a much deeper understanding of cancer, by unravelling its complexity, and learning how it evolves and becomes resistant to treatment.

The ICR is aiming to understanding more about cancer’s genetic diversity and its biology, including about the specific mechanisms that allow cancer to develop, grow and spread.

Crucial too will be taking an overview of how cancer interacts with its environment and adapts to change – including the evolutionary processes which underpin the development of drug resistance.

Cancer’s ability to evolve ways to resist treatment is what makes it so difficult to treat – but understanding the fundamental processes involved could also reveal new vulnerabilities. At the ICR, we are looking to identify new ways to outmanoeuvre cancer and open up exciting new avenues for treatment.

Cancer as an evolving disease

Cancer evolution is not a new idea. Dr Peter Nowell first described cancer as an evolutionary process all the way back in 1976².

What has changed though is our ability to demonstrate cancer evolution in action, by using modern technologies to track the accumulation of specific mutations, and to characterise their effects.

A pioneer of our understanding of cancer evolution is Professor Mel Greaves, who has worked at the ICR since 1984, focusing largely on leukaemia.

Professor Greaves’s research was crucial to unravelling the fundamental biology, potential causes and evolution of leukaemia.

He worked on the genetics of cancer stem cells – cells that can divide repeatedly and develop into many different cell types. His research demonstrated that these cells accumulated mutations dynamically over time – and were constantly competing with each other³.

Professor Greaves found that individual cancer stem cells appeared to act as ‘units of evolutionary selection’ and were responsible for the cancer’s overall behaviour – influencing what mutations become the most prevalent, how the cancer spread and whether it developed drug resistance.

Professor Greaves says he believes it has become clear that “evolutionary principles pervade everything". He describes it as a “wake-up call’ to cancer researchers about the complexity of the disease”.

Scientists like Professor Greaves have helped make the ICR a pioneering institute into cancer evolution.

But we need to do more.

Our new Centre for Evolution and Cancer brings together researchers from evolutionary biology, bioinformatics, genomics and clinical oncology to predict cancer’s next steps.

For example, Dr Andrea Sottoriva is using genomics and mathematical modelling approaches to understand cancer as a complex system. His aim is to be able to predict the path of cancer evolution from a single biopsy sample.

He explains, “By understanding the mathematical rules that govern cancer evolution we can anticipate cancer’s next move and change treatment accordingly. This will help us find new ways to disable or prevent drug resistance.”

Dr Andrea Sottoriva explains how the first pillar of the Research Strategy aims to tackle the problem of cancer evolution and adaptation to treatment.

Cancer and its environment

Another area of complexity that needs to be investigated further is how cancer cells interact with their environment.

A tumour’s surroundings – whether it consists of immune cells, support cells, blood vessels, or even how much oxygen is present – can have a profound impact on its development and behaviour.

The ICR’s goal is to establish an overarching view of cancer’s complex communication networks with healthy cells in its surrounding environment.

For example, researchers at the ICR recently found that pancreatic cancer cells can ‘bully’ neighbouring healthy cells into helping them grow.

Understanding these interactions could help identify biomarkers for resistance and recurrence, and determine which treatments are likely to work best.

Dr Yinyin Yuan is one such scientist investigating these relationships at the ICR.

As the leader of the Computational Pathology and Integrative Genomics Team, her research is looking into whether clinicians can determine the prognosis of advanced ovarian cancer based on the number of stromal cells in the tumour micro-environment⁴.

Dr Yuan’s work shows that a high number of stromal cells, which act as support cells for the body, indicate a worse prognosis.

Ovarian cancer is one of the more difficult to treat cancers as it’s often diagnosed at a late stage – so it’s crucial clinicians find cheap and effective ways of telling which treatments are likely to work and how to predict long-term survival.

Further research at the ICR will reveal how cancers adapt and evolve in response to changes in their environment – including how they evade the immune system and develop resistance to drugs and radiotherapy. 

Using complexity for better treatments

At its core these ambitions serve one purpose – to find better treatments that will save lives.

Understanding the fundamental processes that dictate how cancers occur, change and evolve is essential to the development of these new treatments.

Our research strategy aims to accelerate the progress we’ve made in understanding cancer’s complexity.

This is why our evolutionary scientists are working hand in hand with our drug discovery teams – so that as we uncover new insights into the evolution of cancer, we can apply this to new therapies as quickly as possible.

We will bring together analysis of heritable mutations and tumour genetics, to identify markers of prognosis or treatment response, and new diagnostics.

And we will develop innovative new imaging technologies designed to assess a tumour’s behaviour and metabolism, and to predict or monitor the response to treatment.

All this will give us a far better handle on cancer’s enormous complexity and genetic diversity – and how it takes advantage of that diversity to adapt and evolve.

It is this understanding which can turn evolution from the biggest challenge in cancer research to an opportunity to create exciting new approaches to cancer treatment.

Read more about the Research Strategy

References

1. http://www.cancerresearchuk.org/health-professional/cancer-statistics
2. Nowell P.C. The clonal evolution of tumor cell populations. Science 1976;194:23–28.
3. Greaves M. & Maley C. C. Clonal evolution in cancer. Nature 2012 481, 306–313.
4. Lan et al. Quantitative histology analysis of the ovarian tumour microenvironment Sci Rep 2015 Nov 17;5:16317.