From lemonade stand to grand challenge: changing how we treat cancer in children and young people

Newly funded Cancer Grand Challenges team KOODAC are preparing to do something that’s never been done before. They’ve been awarded up to £20m to develop drugs that break down what actually drives cancer in children and young people. This is the story of how they got here, and the people who made it possible. 

Young children get big ideas. Toddlers make friends with people no one else can see. Their plans for adult life often involve becoming dogs, or aliens. Soon enough, they’re trying to count to infinity. They don’t care what’s possible and what’s impossible: they can change cancer treatment by selling lemonade. 

Four-year-old Alexandra Scott thought up that last idea in a US hospital bed 24 years ago. It’s been coming true ever since. 

Today, Cancer Grand Challenges awarded a research team called KOODAC £20m to develop a groundbreaking new way of treating children’s and young people’s cancers. They’re making drugs to target things that used to be called “undruggable”. Through pain and loss and incredible effort, Alex’s imagination helped them get here. 

One girl’s idea

Back in January 2000, though, Alex, only just four, was lying in an isolation ward in Connecticut, waiting for her immune system to wake up. Her doctors had given her a stem cell transplant to help her recover from the high-dose chemotherapy they were using to treat her nerve cell cancer (neuroblastoma). 

“When I get out of the hospital,” she told her mum, Liz, “I want to have a lemonade stand.” With it, she’d raise money to make sure doctors could “help other kids, like they helped me.” 

They helped Alex as best they could. She liked blue and purple and making clothes. Her favourite animals were penguins and her favourite part of school was all of it. Alex died when she was eight years old, having started a movement that raised $1m for research into children’s and young people’s cancers.  

That was not the end. On what would have been their daughter’s ninth birthday, Liz and Jay Scott established the Alex’s Lemonade Stand Foundation (ALSF). It has since raised over $300m more, funding hundreds of researchers across North America, all working to improve how we prevent, diagnose and treat cancer in children and young people. 

One researcher’s goal

One of those researchers is Professor Yaël Mossé, co-team lead for KOODAC. She’s a doctor and researcher at Children’s Hospital of Philadelphia, which is where she met Alex. She also specialises in Alex’s cancer: neuroblastoma. 

“I think we could tell this whole story through Alex,” Mossé says. She’s being modest. It’s her story, too.

Her part in it started after she saw the shortcomings of the treatments available for children like Alex in the 1990s and early 2000s. Mossé thought she could do more for her patients if she understood what was driving their cancers in the first place.  

In 2008, she found an important link between neuroblastoma and mutations to a gene called ALK. These changes appear in one in four children with high-risk neuroblastoma. Discovering them changed the course of Mossé’s career. 

With funding from the ALSF, she’s since found targeted drugs that can block the messages, or oncoproteins, mutated ALK genes send to make cancer cells grow and divide. In Mossé’s trials, these drugs have stopped some previously “incurable” neuroblastomas in their tracks, allowing children to live healthy lives beyond cancers that doctors thought would kill them. 

Alex, ALK and after

Recently, researchers had the chance to test samples from Alex’s tumour for ALK mutations.

No one knew to look for these changes during Alex’s lifetime. There were no treatments to target them, either. So, like the children diagnosed with neuroblastoma 10 years before her, and those diagnosed 10 years after, Alex was treated with very strong chemotherapy drugs. These can be very effective at killing cancer cells, but they’re also toxic to healthy ones. Alex had her stem cell transplant because of the damage her treatment did to her blood.

“Chemotherapies target rapidly dividing cells, whether they come from normal tissues or cancers,” explains Mossé. “That means there are short-term and long-term side effects for these children, whose organs are still developing.” 

Targeted cancer growth blockers like ALK inhibitors can reduce these side effects because they’re designed to act on cells with very specific features. Most neuroblastomas don’t have those cells, but Alex’s neuroblastoma did. The work she started led to a treatment that could have saved her life. 

Her mum never expected that.  

“I had this leftover idea that we were never going to figure out how to cure her,” Liz says. “I don’t want to say it, but I thought this would be another disappointment – that nothing would have changed. But things could have been different. It was really a big moment for us, as parents. It felt like real tangible progress.” 

That’s often how progress happens: slowly and quietly – smuggled in among the disappointments. Cancer is made of our cells; it’s as complicated as we are. It takes time, effort and bravery to work it out. But every act of generosity counts, and we’re always learning from what came before.  

“This is really the heart and soul of what we do,” says Mossé. “We get inspired by our patients, we take that motivation into the lab, and then we take what we learn back to the patients.” 

In other words, the belief and commitment of a little girl we lost 20 years ago can help children in her position grow up tomorrow.

Today, though, we have a chance to do so much more.  

There are new drugs on the horizon. They could rapidly change how we treat multiple types of children’s and young people’s cancer. It will take millions of pounds and continents of expertise to get to them, but that’s what Cancer Grand Challenges can provide. 

Targeting cancer in children and young people

First: the problem. The targeted cancer treatments Mossé has tested so far weren’t actually developed for children. Her breakthroughs came from repurposing drugs designed to help adults with non-small cell lung cancer, which can also be driven by changes to ALK. 

Things rarely line up that well. Because cancers in children and young people usually start in developing cells, rather than mature ones, they tend to involve different genetic changes than adult cancers. These changes are also harder to target with drugs, meaning we have fewer treatment options for solid tumours in children than we do in adults. 

But some genetic changes show up in all age groups. One involves a gene called MYCN, which mutates to drive the growth of lots of different types of cancer. In neuroblastoma, it often works in tandem with ALK, limiting the number of children than can benefit from Mossé’s treatments. 

KOODAC’s other team lead, Professor Martin Eilers, from the University of Würzburg in Germany, has spent his career studying MYCN. Scientists have known about it for more than 40 years, he explains. They’ve written enough papers on it to fill a library.

Still, because MYCN sends different types of messages than genes like ALK, no one has found a way to block it. Somewhere along the line, people started calling it “undruggable”. 

Eilers never believed that. Nor did Mossé. They had seen how targeting ALK mutations could help children with neuroblastoma, so they put together a team and went to the ALSF with a plan to stop MYCN driving these cancers, too. In the spirit of Alex’s big idea, the charity gave them one of its special “Crazy 8” grants to do just that.

From undruggable to degradable

Drugmakers had tried and failed to block the protein messages mutated MYCN genes can send to cancer cells. Mossé and Eilers decided to investigate a new drug technology with the potential to shred them.  

The Crazy 8 grant showed that that was possible. Now, with the funding from Cancer Grand Challenges, KOODAC will put it into practice. 

They’ll be developing new protein degrader drugs against 5 different oncoproteins, including both MYCN and ALK. Together, these drugs could drastically improve how doctors treat children and young people with neuroblastoma, fibrolamellar hepatocellular carcinoma, medulloblastoma, Ewing sarcoma and rhabdomyosarcoma. 

In one sense, it’s a revolutionary step forward. In another, it’s what we’ve always been doing. As surely as children find strange things in their imaginations, our cells get rid of proteins we don’t need.

They have to. Almost all the things our cells do involve making proteins. They can’t let those proteins hang around when their jobs are finished. That would be like everyone in your house deciding not to clean up after eating. Within a week, the kitchen’s mouldy and cluttered and there’s nothing left to eat off.

Cells aren’t too different. Apart from in size, that is – and you need to be even more careful about cleaning up in small spaces. You might even want to find ways of using the same things for different tasks. Once they’re finished with proteins, our cells degrade them into the tiny pieces they need to make new ones.  

It’s recycling. All our cells are doing it all the time.

“It’s an inherent process,” explains Eilers. “The same way our bodies are always making things, we continuously degrade proteins that we don’t need.”

We definitely don’t need cancer driving proteins, but they’re so unusual they don’t attract the attention of the waste-disposal system. Degrader drugs just point them out, and then the system does its work. 

Better drugs with fewer side effects

In the first place, this means degraders can affect previously undruggable targets like MYCN oncoproteins. They should also work better against the messages sent by ALK. Whereas inhibitor drugs leave dangerous proteins intact (which means they can break loose and find a new way to deliver their messages), degrader drugs get rid of them completely. 

What’s more, because degraders specifically target the features of oncoproteins that make them stand out from healthy proteins, they should cause far fewer side effects. 

“This is an opportunity to target precisely the drivers of these childhood cancers,” explains Mossé. “And, as these proteins are expressed mostly just in the tumour and not in healthy tissues, we have a chance to go after them without causing children harm.”

Everyone’s futures

Liz understands that potential as well as anyone. It’s why, as well as running the ALSF, she and her husband Jay decided to join KOODAC as patient advocates. 

“I don’t usually love being a patient advocate because it takes so much time,” she says. “Every hour is so important when you’re fundraising, but I couldn’t resist being part of this. Now we’re crossing borders and bringing more organisations together to solve these problems. That’s exactly what we need.” 

Cancer touches all of us. It’s not something we can face alone.

“I think Yaël said this story could be told through Alex because Alex stands for so much. But she’s just one child. It’s every child: that’s what this means to me. 

“It’s about this community – and it’s more than an oncologist in Philadelphia and a biochemist in Germany, as well. The kids are part of the community, and the parents are part of the community.  

“Alex started this with a simple idea, but the magical thing is how people come together, and the work that’s being done to make the idea so much bigger.” 

Every child has big ideas. They might save lives, or they might just make you smile.  

We’re working so more children can see where their ideas lead. 

Tim