Image: Professor Sir Mel Greaves in one of the buildings on the ICR's Sutton site
Professor Sir Mel Greaves, Founding Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, London, is responsible for some of the most significant recent developments in childhood cancer research, but he is still well aware of the difficulties in this area.
“You have to be an optimist to be in this field of research,” he said. “There are many biological and clinical challenges in paediatric cancer.”
The first of these is that cancer advances rapidly in children, so it tends to be picked up at a later stage. This issue is compounded by the fact that the first symptoms of cancer are often similar to those of other, more common conditions, such as viral colds. In addition, the relatively low incidence of childhood cancers means that no screening programmes are in place to detect them early.
A further complication is that the cells and tissues in young children are very sensitive to the toxic effects of drugs. To avoid affecting patients’ growth and development, treatment dosages must be limited, which restricts what can be achieved. Unlike in older adults, the aim is to give children lifelong health, not just prolong their lifespan.
On top of this, some cancers are so rare that they affect only a few children each year. This makes it difficult to collect enough data on the disease to build a thorough understanding of it and work towards developing effective treatments.
“My children were my primary motivation”
Many cancer researchers credit their desire to improve the lives of patients with motivating their day-to-day work in the lab or clinic. But this only works if they believe that their work will make a difference, and it can be particularly difficult to hold onto this belief in childhood cancer research.
Sometimes, a strong driving factor is needed. In Professor Greaves’ case, this was his children.
“In the 1970s, I visited Great Ormond Street Hospital,” he said, “where I met several young patients with leukaemia who were clinging tenaciously to life. My own children were, at the time, the same age, and the realisation that I could instead be visiting the ward as a father inspired me to focus on childhood leukaemia.
“I think if you’re a parent and you see children undergoing chemotherapy, it’s impossible not to consider that it could be your child. That emotion has really sustained me throughout my career.”
Another essential factor for any researcher is their team. Professor Greaves said:
“Science is a very social activity, requiring a multitude of skills and effective collaboration. Throughout my career, I have surrounded myself with colleagues and collaborators who have their own skill sets but share the same underlying motivation. This has facilitated an open forum and allowed us to support, respect and value each other’s work, meaning we can achieve more together.”
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The power of motivation
When Professor Greaves first started working on leukaemia, the disease carried a high mortality and morbidity burden. Prior to the 1960s, all childhood leukaemias were completely incurable, and even when treatments became available, they came with severe lifelong side effects.
It was a significant challenge that would have been too daunting for many to take on. But Professor Greaves knew that if he wanted to change the lives of children with leukaemia, he just needed to make a start.
“There is no secret,” he said. “There’s no formula to success. But you need an all-consuming passion for science, as well as the confidence to follow your intuition. On top of that, you need the tools and necessary support infrastructure.”
Professor Greaves was inspired by Charles Darwin, whom he praises for being “audacious enough to risk asking a big question” and then “doggedly pursuing it for the next 30 years.”
And Professor Greaves has done just that, asking perhaps the biggest question in childhood cancer – might it be possible to prevent leukaemia? – and relentlessly chasing down the solution for decades.
Image: Journalist and broadcaster Victoria Derbyshire interviewed Professor Greaves about his long and prestigious career at an event organised by the ICR.
Working towards preventing leukaemia
After seeing young children going through tough treatment regimens in hospital, Professor Greaves knew that he wanted to do everything in his power to relegate the disease to the past. This might have seemed overly ambitious to some people, but Professor Greaves believed that it was achievable.
“In leukaemia, our experience with acute lymphoblastic leukaemia (ALL) had already taught us that we can provide a cure,” he said. “The survival rate is now higher than 90 per cent for some ALL subtypes, even though the disease is intrinsically very malignant. Without effective treatment, the survival rate would be virtually zero. It’s enormously encouraging to know that a malignant cancer in children is curable.”
Through his work, Professor Greaves was able to pinpoint the likely cause of ALL, which now underpins his aspiration to prevent childhood leukaemia from ever developing.
“The development of leukaemia is a two-hit process,” explained Professor Greaves. “First, a mutation occurs in a blood cell in the developing foetus in the womb. This leads to pre-malignant cells that expand but are not cancerous and can stay silently in place for 15 years.
“The second hit is a mutation that usually occurs in children aged three to five, and this rapidly leads to the overt clinical disease and a diagnosis. Common infections in young children seem to trigger this second hit, but, critically, only if the child’s immune system was inadequately primed by microbes during infancy. That microbial function is provided by the gut microbiome and its constituent bacteria.”
Professor Greaves believes it may well be possible to prevent leukaemia by ensuring that babies have microbial exposure to prime their immune system. Once the necessary bacteria have been identified, scientists may be able to develop a drink for children to take in the first months of life. As well as preventing leukaemia, this simple prophylactic strategy might also reduce the risk of type one diabetes, other autoimmune diseases and allergies in children and young adults. These conditions, extraordinarily, share many of the same lifestyle risk factors linked to the immune system as childhood ALL.
Image: Microbial exposure helps prime children's immune systems. Credit: Jill Wellington from Pixabay.
Other developments are improving outcomes too
His proposition, which was published in Leukemia, a Nature journal, represents a huge step forward in childhood cancer, but it is not the only one. Professor Greaves noted that a form of immunotherapy called chimeric antigen receptor (CAR)-T cell therapy, which is used to treat some types of paediatric leukaemia, is also a noteworthy development. He said:
“Some very difficult-to-treat leukaemias have responded very well to this treatment. The results are quite dramatic for some children, and the treatment is less toxic than other options, so it looks very promising.”
The treatment involves multiple stages. First, clinicians take a sample of T cells – a type of white blood cell that fights infection – from the patient’s blood. They then genetically engineer these cells to create CAR-T cells that recognise and target a specific protein on the cancer cells. Once the CAR-T cells have multiplied sufficiently, clinicians reintroduce them to the patient’s bloodstream. Examples of these treatments include axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah).
Another type of treatment that has shown potential in recent years is neurotrophic tyrosine receptor kinase (NTRK) inhibitors. These drugs work by targeting a gene called NTRK, which, when activated improperly, transforms healthy cells into cancerous ones. Such treatments, which include entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), can be used to treat children with solid tumours that display an NTRK gene fusion.
Curing cancer kindly
Developing a new treatment is not the only way to make a breakthrough. It is also important to refine existing treatments to make them kinder for children.
“Cancer treatment is often horribly toxic,” said Professor Greaves. “Parents often describe it as very debilitating for their child and traumatic for the family.”
In recent years, scientists have brought molecular profiling into tumour diagnostics, which has helped clinicians understand more about each patient’s cancer and how it is likely to progress. With this knowledge, clinicians can focus intensive therapy on only the most aggressive cancers, using a gentler approach for low-risk tumours to minimise side effects. In some cases, they can use targeted therapies that will be more effective against the identified tumour subtype.
This development may help improve outcomes for many young people with cancer. For instance, in a 2022 study, researchers performed molecular tumour profiling for 345 paediatric patients with solid tumours outside of the brain and found that 86 per cent of them had at least one genomic alteration with the potential to affect their care as a target for therapy. More than 60 per cent of the patients had alterations with diagnostic, prognostic or therapeutic significance.
Researchers at the ICR are among those leading the way in this area. Professor Louis Chesler, Leader of the Paediatric Solid Tumour Biology and Therapeutics Group at the ICR, is co-leading the Stratified Medicine Paediatrics 2 (SMPaeds2) research programme, which aims to develop advanced genetic tests and analyses that will give scientists extraordinary insights into the biology of relapsed childhood cancers. Such insight will aid precision medicine, helping give children the best possible outcomes.
Alongside these developments, there are other causes for celebration. Survival rates are increasing in some types of childhood cancer, and kinder treatments mean not only that fewer people are experiencing long-term side effects but also that more of their treatment can take place in an outpatient setting.
Patients have also benefitted from various advances in technology. By exploiting these, scientists have for instance found various ways to minimise tissue damage during radiotherapy delivery, including using proton beam therapy in place of radiation, targeting small, centralised areas within large tumours rather than the entire mass, and using MRI to note changes in the body that might require adaptations to the treatment approach. In a more specific example, clinicians can now detect minute amounts of residual leukaemia, helping reduce the risk of recurrence for children with this condition.
Image: Professor Louis Chesler in the lab at the ICR.
Drug resistance continues to be an obstacle
However, at this point in time, progress is not universal, and in some types of childhood cancer, there has been little improvement. Professor Greaves believes that researchers should consider focusing more on one particular area: drug resistance. He said:
“For decades, we’ve been going in at the max, blasting cancer as forcefully as possible. But this, ironically, selects for the evolutionary emergence of drug-resistant cancer cell variants as a weed-like species. Resistance is inherently an evolutionary problem. Ever since they first developed, cells have had to learn how to survive lethal challenge by adopting resistance tactics. We have been trying to outwit almost four billion years of evolutionary resilience in cells and desperately need to work out whether there is a way around this.
“In HIV, clinicians have changed the dosing schedule and drug combination to minimise the risk of resistance while also keeping the disease from progressing. We could adopt a similar approach in cancer, slowing it down to become a chronic disease that is less malignant. This would be an attractive option for older adults with cancer; less so for children with a lifetime ahead of them.”
Adaptive therapy techniques are another option. This approach involves providing enough treatment to reduce the number of treatment-responsive cancer cells without eliminating them. The idea is that leaving some chemo-sensitive cells in place helps limit natural selection for resistant cells.
Many scientists, including Professor Greaves, are also investigating the effects of loss-of-function mutations in the TP53 gene. These mutations, which are linked with drug resistance and poor treatment outcomes represent by far the most common genetic change in cancer. This work is providing Professor Greaves with the opportunity to learn further from ALL and a few other malignancies, such as favourable Wilms tumours in children and testicular cancer, which all lack TP53 mutations and are close to 90 per cent curable. His team recently published a paper in BMC Ecology and Evolution, which concludes:
“The evolutionary resilience of advanced cancer, consistently and convergently empowered by TP53 loss, is arguably the biggest barrier to therapeutic cure or control.”
In another recent perspective piece, published in Nature Ecology & Evolution, Professor Greaves and his co-authors state that although the specific solution will vary across cancer types, “evolutionary steering of cancer clones into more benign or drug-sensitive directions offers great promise for more effective control if not cure.”
“This is not the end”
Still sustained by his original motivation, Professor Greaves is not hanging up his lab coat just yet, despite having dedicated about 50 years of his life to cancer research already. He stands by what he said when he was awarded a Royal Medal in 2017:
“I feel very privileged to have been in a position to contribute towards the unpicking of this once mysterious and lethal disease in children. Childhood leukaemia was once considered to be universally fatal, but thanks to the tremendous research progress made over the past 40 years, treatment is largely successful. This is not the end, though – I am as excited and engaged as ever by my work, and there is still so much to be done.”
Each of our researchers at the ICR has their own incentive to keep contributing to the mission to defeat childhood cancer. Many of them are inspired by their own personal experiences or by those of our fantastic family charity partners, whose strength in the face of adversity is both humbling and inspiring.
Thanks to our scientists’ work and the generosity of our funders, supporters and donors, the ICR can continue doing everything possible to improve the quality of life and outcomes of all children with cancer.
We are world leaders in the study of cancer in children, teenagers and young adults and have made huge strides over the past decade in improving treatment options for children with cancer.
This progress is made possible by long-term investment in this area of research, including from our supporters and family charity partners.
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