‘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.