‘The Wings of Science’ – a story of basic research with real life impact

5 Feb 2021 11:05

What do Dutch researcher and Oncode Investigator Rene Bernards (NKI) and British columnist and podcaster Deborah James have in common? They are both on a mission to fight cancer. Bernards’ ultimate goal is to bring his research findings to the clinic and by that to impact people’s lives. James turned her own stage 4 bowel cancer diagnosis into a mission not only to fight the illness but also to change the conversation around it. The two met in 2018: as James was running out of treatment options, it was Bernards’ innovative therapy that came to her rescue. (text by Oncode)

‘I have it in my genes somehow, to want to translate my findings into solutions in the clinic’ says Bernards at the beginning of our interview. ‘I find it more rewarding to do that, than to publish in a top journal. Don’t get me wrong, I think it’s nice to publish. But to me that is a bonus. What I really care about is the clinic. And when I focus on that, the publications come too, he adds.
Almost nine years ago, Bernards and his colleagues at the NKI made a discovery that was published in Nature. Together, they had unravelled a ‘clinical mystery’. The BRAF gene mutation was known to occur in several cancers, the most frequent one being melanoma skin cancer. In this type of cancer, the BRAF inhibition is very effective as a single agent therapy. Drugs against the BRAF oncogenic protein have been developed and they work. But the same mutations in the BRAF gene also occur in about 10% of colorectal cancers and logic would say the same drug would work for it too. Yet studies showed it did not. At all.
Bernards' lab took on the challenge to understand why. The question was to figure what else should be inhibited besides the BRAF oncogenic protein. The answer that led to the Nature publication in 2012 – was that a second protein needed to be inhibited, one called EGFR. ‘We were very fortunate that inhibitors of the EGFR were already clinically available and already approved for use in colorectal cancer’ remembers Bernards. ‘It was just a matter of combining two already existing drugs. In combination, the two worked in humans exactly as they worked in mice. But the interesting part is the two drugs individually had zero effect. It was really a case of minus times minus equals plus. That is a rule we can accept in math but of course, in the clinic, it would seem ridiculous that two drugs that have no effect separately, in combination would have a strong effect. But that was nevertheless what we saw’ he adds.

The team got a clear understanding of why, mechanistically, the combination became highly effective. ‘It is a novel process called synthetic lethality. It means that two events that individually are nonlethal become lethal in combination. Two drugs that don’t kill suddenly become lethal in a cocktail.’

The team proved its efficiency in animals and then together with clinicians went out to speak to pharmaceutical companies to convince them to do a clinical proof of concept study, eventually leading to the BEACON trial. It was this trial that saved Deborah James’ life.

James found out in December 2016, at the age of 35, that she had stage 4 colorectal cancer. But not the usual type - she has this rare BRAF mutation found in only 10% of the cases. The mutation makes it an aggressive form of cancer, the one that is most difficult to treat. This type of cancer gets used to treatments quickly, it is unresponsive to chemo, leaving few options.

Since the diagnosis, James has been not only battling the disease but also the misconceptions around living with cancer. ‘When I was diagnosed, I was desperately searching for stories like my own, and they just weren’t in the public eye. Cancer is still a taboo. The misconception is that you get cancer and then you die from it. Speaking about it means changing this perception, turning it also into a conversation about actually living with cancer. And it is also a way of celebrating science and how far we are coming with science’.

Only 10% of people having colorectal cancer with the BRAF gene mutation survive five years or more. Five years later, Deborah is about to beat those odds. In 2018, James met Bernards. And when things seemed to go down, her oncologist fought for her to be part of the BEACON trial on compassionate grounds. The drug combination worked.

‘I’m living when I shouldn’t be’ she recently said, thanking Bernards on the British TV show Lorraine. Knowing him draws for her what she calls ‘a full circle’. ‘I think we all need to know why we are doing what we do, and researchers also need this reminding. That what they do helps people like me’. ‘Clinicians are more used to that’ said Bernards when asked how being thanked for his work made him feel. ‘But as a basic researcher you have less exposure to these real life changes that these diagnostics and therapeutics can have’ he adds. ‘In the end we need to realize that this is why we are doing research. We publish research to improve the life of cancer patients.’

The therapy is now approved as standard of care in Europe and the United States. But getting it approved was a long process. ‘I think if the therapy is really effective, you know after 10 patients that it works. The rest of the process is getting the statistical significance that will convince regulatory authorities. We published the pre-clinical data that suggested this drug combination was very active in 2012 and within two years we had a clinical proof of concept study that showed beyond doubt that this was going to become standard therapy. Yet it took 6 more years to get the regulatory approval’ says Bernards.

He sees how these days, Oncode comes in to help speed up the process. ‘Now we have the Oncode clinical proof of concept fund (CPoC) and that helps a lot, because that allows you to jumpstart a clinical study without depending on third parties. That is always a big bottleneck’ he says.

James will turn 40 this year. She continues her battle with the illness and her frontline advocacy – writing an award-winning weekly column in The Sun online, campaigning and fundraising alongside major UK cancer charities and writing and presenting the awarded chart-topping podcast ‘You, Me & the Big C’ for BBC Radio 5 Live. On Instagram, she calls herself ‘@Bowelbabe’ and documents first-hand the experience of living with cancer.

Bernards on the other hand is back in his lab, busy scouting for other effective combinations. ‘Through my base fund from the Oncode Institute I was able to develop a new and highly effective combination for liver cancer that I am working on, he says. ‘Because I could spend the base fund of Oncode the way I thought I should, I was able to do more of these pre-clinical studies, that I thought would deliver patient benefit’ he explains. ‘Oncode helped me in more than one way. It gave me the freedom to pursue the new clinical questions linked to unmet needs that I thought were important, and the CPoC funding helps quickly translate our discoveries into small patient studies, demonstrating that our discovery really works.’