Malignant melanoma – a type of skin cancer – is almost always curable when it’s found in its very early stages. Unfortunately, it’s far more aggressive than other skin cancers and often becomes metastatic – spreading to other parts of the body. When it reaches this stage, it becomes almost untreatable, and is nearly always fatal.
Until recently there were no effective treatments for metastatic melanoma, but in the last decade we have seen a flurry of treatment breakthroughs, and scientists at the ICR have been at the heart of the fight against the disease.
We began to focus our research on melanoma around 15 years ago, when a team of scientists at the ICR discovered that the gene for a protein they were working on – BRAF – was faulty in approximately half of all cases of melanoma. BRAF creates a protein which tells cells when to grow and divide, so when the gene is mutated it keeps the growth signal permanently ‘on’ – allowing cells to multiply unchecked. Finding a way to shut down this growth signal which fuels the development of cancer became a priority for researchers at the ICR and worldwide.
Work over the next decade led to the development of a number of small-molecule inhibitors targeting a mutated BRAF gene. Vemurafenib – the development of which was underpinned by ICR science – was the first effective treatment for patients with metastatic melanoma. But while BRAF inhibitors often work very quickly to control melanoma, the problem is that the cancers usually become resistant to treatment within a year. So while the development of BRAF inhibitors has been a big breakthrough, they represent the beginning, rather than the end of the story. The battle against malignant melanoma is only just starting.
Professor Caroline Springer, Professor of Biological Chemistry at the ICR, is now continuing the fight against melanoma. She is collaborating with Professor Richard Marais – now at the Cancer Research UK Manchester Institute and previously heavily involved in the BRAF discovery while at the ICR – to design new drugs which may overcome the problem of BRAF resistance.
The researchers have recently published their work on a brand new family of cancer drugs called ‘pan-RAF’ inhibitors, which are designed to block several key cancer-causing proteins at once. These new compounds not only inhibit the BRAF protein, but also inhibit other RAF proteins implicated in cancers, and could potentially treat incurable skin cancers.
“Our work showed that our pan-RAF inhibitors stopped the growth of BRAF-driven melanomas, including those that had stopped responding to currently available BRAF-targeted drugs,” reveals Professor Springer. “But we also saw that our new inhibitors stopped tumour growth in cancers where BRAF-targeted drugs had failed to work – which happens in around 20% of cases.
"After further investigation, we saw that these new inhibitors work because they block multiple cancer proteins at once – targeting both BRAF and the growth pathways that the cells come to rely on when they become resistant. In effect our new inhibitors deliver multiple blows to knock out cancer, and they are a major gain compared with the drugs on the market.”
The next stage will be to move one of these inhibitors into clinical trials so we can establish that it is both safe and effective in cancer patients – hopefully this year. If successful, pan-RAF inhibitors could treat drug-resistant skin cancer, giving hope to thousands of patients who have run out of treatment options. While the battle is not over yet, the initial success of pan-RAF inhibitors has certainly given hope in our fight against melanoma.