How can we avoid cancer?

Sarah Knight – a Canadian British New Zealander – lives in Cambridge with her husband and two children. When we met at her home, Sarah told us she had recently finished chemotherapy and immunotherapy after being diagnosed with breast cancer last year. She said she was still experiencing some cognitive issues, and the chemotherapy had knocked 20 points off her IQ. On top of that, she shared that only three weeks earlier she had had a hysterectomy – surgery to remove the uterus – to reduce the risk of cancer coming back. I was surprised to hear she was recovering from surgery, and still suffering from the side effects of chemotherapy, given how well and bright she looked.

While we chatted, touching on international politics, travelling around New Zealand and what day-to-day looks like working in science communication, we moved onto the topic of genetics. Sarah shared that she has Lynch syndrome, a genetic condition that significantly increases someone’s risk of developing several cancers – most commonly colorectal and endometrial cancers. It is caused by a genetic mutation in a mismatch repair gene, which causes our in-house DNA repair mechanisms that fix mistakes in the genome, to go faulty. Lynch syndrome is inherited, and people usually find out they have it through genetic testing.

Sarah reflects: “The silver lining to having breast cancer treatment and genetic testing was finding out that I have Lynch syndrome. Finding that out helped me, as I lost my sister to cancer 10 years ago. She had a cancer of unknown origin. Nobody could tell us what the cancer was, why she had the cancer, or how to treat it. But now we finally have some answers, and I am fascinated by how far we’ve come in 10 years, and how genetics is moving ahead so quickly.”

Despite her cancer diagnosis and loss, Sarah remained positive as we continued chatting in her living room. She still considers herself lucky.

“I feel like I've always been a lucky person. When I was a little kid, I looked for four-leaf clovers in the grass and I found lots of them. I would put them on little cards and write my name and when they were found, I carried them around as proof that I was lucky. And having a cancer predisposition gene doesn't impact that – I still feel lucky. I want to find what's lucky about this because I'm convinced that there are good things to come from it.”

Sarah believes that the more information we have about cancer, the more empowered we can become to manage it, or avoid it. That is one of the reasons she is joining five other patient advocates on the Cancer Avoidance project. Spanning from the UK to Japan, they are all involved from the start – working closely with the scientists to inform the research plans, and to help ensure the findings down the line are relevant and meaningful to them and other patients.

“It surprised me that research is truly interested in the patient voice and patient involvement. It is really exciting from a patient perspective that our voices are heard and that they're truly valued,” Sarah expressed.

Cancer avoidance means different things to different people. For patients, it could be choosing which food or drinks they consume or avoid, or what lifestyle choices they make to boost their health. And for people like Sarah who have a cancer predisposition gene, it could mean undergoing preventative surgery to try and minimise the risk of getting the disease, or it coming back.

For scientists, cancer avoidance dives deeper down to the level of tissues and narrows down to individual cells. Every day our cells are working hard to defend against cancer-causing exposures. Dr Jyoti Nangalia, Group Leader at the Sanger Institute is hoping to uncover how our cells are intrinsically avoiding cancer on a daily basis. Also, as Consultant Haematologist at Addenbrooke’s Hospital in Cambridge, Jyoti believes that we can harness our natural defence mechanisms to find new ways to understand and treat cancer, or even prevent it from happening in the first place.

Jyoti says: “What motivated our project is a paradox at the heart of cancer biology. If you take individuals that are at a very high risk of cancer, perhaps because they were born with an inherited risk for cancer – like a defective BRCA gene – or may have been heavy smokers, most of their tissues and organs do not actually go on to develop cancer. This suggests that there are protective mechanisms that are active every day in our body, protecting us from cancer.”

Jyoti is working with an interdisciplinary team, from across the globe, on the Cancer Avoidance project. To investigate our natural defences, the team will study three groups of people that represent the extremes of cancer risk. They will analyse tissue samples from individuals at high genetic risk of cancer – such as those with a BRCA genetic mutation, or with Lynch Syndrome; people who are at high environmental risk of cancer – including long-term smokers; and Japanese super-centenarians – those over 110 years old that seem to be naturally resistant to cancer.

The researchers will initially focus on studying tissue from four organs – blood, colon, breast and lung – which all differ in how they regenerate, interact with the immune system and respond to environmental exposures. Within these individuals, they will study the cells that developed cancer, alongside the millions of healthy cells that resisted it. They want to ultimately understand what protected those healthy cells, even though they were genetically similar and faced the same exposures to those that developed into cancer.

Jyoti and team already have some clues that are guiding their research. While they will explore various interconnected cancer defence mechanisms in our tissues, they will particularly focus on three: ‘protective’ mutations, natural anti-cancer barriers and the immune system.

Mutations, mutants, mutated beings – these terms usually conjure up negative images and thoughts of disease and science fiction. Understandably, most people think that mutations are a bad thing, but the fact is that all of our cells are accumulating mutations – or genetic ‘typos’ – across our genomes over the course of our lifetimes. They are a way of life.

Research has shown that some of these mutations can be beneficial and actually protect cells from subsequently developing into cancer. For example, a protective mutation in the NOTCH1 gene –which controls how cells grow and communicate, and is found in most cells of the human oesophagus – reduces tumour growth.

Using cutting-edge genome sequencing on thousands of samples at the Sanger Institute, the team will find beneficial ‘cancer-avoiding’ mutations that protect vulnerable cells from cancer and trigger the death of unwanted rogue cells. The researchers hope that if they can identify these ‘protective’ mutations and understand how they work, then they could develop treatments that mimic them and protect our cells, preventing them going down the path towards developing cancer.

Many of our tissues have physical barriers that protect them from chemicals or other exposures that may lead to cancer, with some tissues being naturally better protected than others. The team will study cells in the colon that secrete chemicals that shield against bacterial toxins, proteins in the lung that neutralise tobacco smoke, and hormonal interactions in BRCA-mutated tissues that make some organs succumb to cancer, and others more resilient. By understanding how various barriers work, they can explore ways to reinforce and strengthen these defences in at-risk individuals, to give them the best chance of avoiding cancer later on.

Our immune system is constantly on the lookout for foreign or abnormal cells, including cancerous ones, which it then kills. Boosting the body’s own immune system to find and destroy cancer cells is a more recent type of cancer treatment known as immunotherapy.

Rahul Roychoudhuri is Professor of Cancer Immunology and Immunotherapy at the University of Cambridge, and co-investigator on the Cancer Avoidance project. His team will map how specific immune cells recognise and destroy mutated cells, known as mutant clones, in tissues like colon, breast and lung – before cancer has had a chance to progress. By imaging immune cells within expanding mutant clones across tissues and validating their results in experimental model systems, including human organoid cultures, they aim to pinpoint which immune responses are most protective, in which parts of the body, and crucially – at what time points. The team ultimately aims to explore ways to enhance our immune system to protect vulnerable organs in those people who are at a particularly high risk of cancer.

Rahul is excited to be part of the Cancer Avoidance project: “By the time cancer cells have developed into large established tumours, they're very good at hiding from the immune system and suppressing its activity. What's exciting about this project is that we're looking much earlier at normal tissues that are at risk of cancer, before the disease has progressed, because we think the action of the immune system starts there. If we can understand the ways in which the immune system interacts with tissues at risk of developing cancer, we hope to be able to design new treatments that strengthen the immune system in high-risk people to prevent them getting the disease in the first place.”

This project is a mammoth undertaking, which cannot be completed by one team or institute working alone. Jyoti and Rahul are joining forces with other leading scientists from the UK, US and Japan to build an international Cancer Avoidance community. Each collaborator on the project brings essential complementary expertise – from world-leading genome sequencing, to advanced organoid and mouse modelling, and immune cell profiling. All of the findings will be combined and integrated to create an AI-driven ‘Cancer Avoidance Index’, led by Professor Jamie Blundell from the University of Cambridge, which can be used in clinical trials to predict which patients are most at risk of developing cancer and reveal why some patients remain protected.

By combining their collective skills, openly sharing data and partnering with inspiring patient advocates from across the globe, the Cancer Avoidance team will begin to unravel and strengthen the body’s natural resilience to cancer.

Jyoti explains why the international community behind the project is so important: “To truly understand how to avoid cancer, we need to look beyond one country. Cancer rates vary around the world – some countries have very high rates of cancer for one particular organ, but very low rates of cancer for another. And if we could understand why that is, in what ways it relates to the environment or the genetic makeup of those populations of people, we could find new ways to avoid certain cancers that could then be applicable across the globe.”

What does this project mean for the future? For researchers, it will launch a new field of cancer resilience biology. For patients, this research promises a profound shift, from one of fear of cancer risk to a positive outlook on cancer resilience. For clinicians, it will create a future that moves away from reactive treatment to proactively reducing risk of disease. This could mean monitoring for people with inherited or environmental risks, the creation of new predictive models to decide when to intervene with treatment, and new drugs that specifically target cancer cells and protect healthy ones.

Jyoti’s vision for the future is inspiring: “Our ultimate vision with this Cancer Avoidance project is to find new ways to protect cells from cancer. This will shift the focus away from a fear of cancer to one that empowers people to be resilient against the disease in the first place.”

Meanwhile, Sarah shares her hopes for the future: “I believe that there will be discoveries made from this research that will allow us to see the things that are protecting us from cancer rather than just see the things that are causing the cancer. In the future, in my wildest dreams, people aren't afraid of learning about their genetic makeup. And we can learn how to protect people so that everyone has the chance to live a long, healthy life – hopefully into their eighties – and to see their children grow.”

“I believe that there will be discoveries made from this research that allow us to see the things that are protecting us from cancer rather than just see the things that are causing the cancer.”

Sarah Knight,
Patient Advocate, Cancer Avoidance Project CRUK Grand Challenge

Meanwhile, Sarah shares her hopes for the future: “I believe that there will be discoveries made from this research that allow us to see the things that are protecting us from cancer rather than just see the things that are causing the cancer. In the future, in my wildest dreams, people aren't afraid of learning about their genetic makeup. And we can learn how to protect people so that everyone has the chance to live a long, healthy life – hopefully into their eighties – and to see their children grow.”

This work has been shortlisted for a Cancer Grand Challenges award. Find out more here.