18 June 2013
A strain of virus used to vaccinate millions of people against smallpox could significantly improve the treatment of aggressive skin cancer, a new study reports.
Scientists at The Institute of Cancer Research, London, found the GLV-1h68 virus - a modified version of the vaccinia strain used safely across the world as the smallpox vaccine – was able to effectively kill cancer cells when combined with radiotherapy.
Malignant melanoma, the most aggressive form of skin cancer, kills over 2,000 people in the UK every year and is difficult to treat with current therapies. But oncolytic vaccinia viruses have the remarkable property of being able to selectively target and kill cancer cells.
Previous studies have suggested they might be useful as a treatment against melanoma as they manipulate host-signalling pathways present in melanoma cells to grow and spread more quickly than in normal cells.
Researchers at The Institute of Cancer Research (ICR) combined the GLV-1h68 virus with radiotherapy to kill melanoma cells much more effectively than the two treatments separately.
This effect was only found in melanoma cells displaying the BRAF mutation, which accounts for about 50% of all melanomas.
The researchers, funded by the Myfanwy Townsend Melanoma Research Fund and the Rosetrees Trust, hypothesised that using radiotherapy in conjunction with the modified virus would act to turn the heat up on these host-signalling pathways, allowing the virus to grow better in melanoma cells and increasing the effectiveness of combined treatment.
They tested the combination of radiotherapy and the modified virus on a panel of melanoma cell lines, but the virus did not grow more quickly as the team expected. Instead, in melanoma cells with the BRAF mutation, the virus grew more slowly but radiotherapy enabled the virus to kill cells faster and more efficiently.
When they treated mice with both GLV-1h68 and radiotherapy, their tumours took much longer to grow than with either treatment separately. Taken together this preclinical study suggests that combining therapies is a promising approach for treating malignant melanoma.
Professor Kevin Harrington, Joint Head of the Division of Radiotherapy and Imaging at The Institute of Cancer Research, London, said: “Malignant melanoma has often been viewed as an untreatable disease because it doesn’t respond well to conventional chemotherapy or radiotherapy, but our work at the ICR has advanced our understanding of the causes of skin cancer by defining how the protein BRAF triggers cancer.”
The team found that the JNK and TNF-α signalling pathways normally activated by the virus in BRAF melanoma cells were switched off when radiation was combined with the modified virus. TNF-α secretion acts as a survival signal for cancer cells with the BRAF mutation, so switching off its production resulted in a significant increase in cell death for the combined treatment.
To prove the JNK pathway was responsible, researchers mimicked the effect of radiotherapy by using a chemical JNK inhibitor to silence this pathway in BRAF mutant cell lines, producing the same results as combining the virus with radiotherapy. In melanomas without the BRAF mutation, the radiation failed to silence the JNK pathway, so radiotherapy did not increase the effect of GLV-1h68 treatment.
Dr Joan Kyula, Post Doctoral Training Fellow in Cancer Biology at The Institute of Cancer Research, London, said: “We know that vaccinia viruses have the ability to kill cancer cells, but now we have shown we can get an even better effect in melanoma by combining with radiotherapy. Using the GLV-1h68 virus with radiotherapy killed BRAF mutant melanoma cells more quickly than either treatment alone, providing clear evidence for offering both treatments to patients with this type of the disease.
“What’s more, being able to replicate the effects of radiotherapy chemically shows that we understand the growth mechanism in BRAF mutated melanoma. This study provides promising results in the laboratory, the next step will be to continue research and develop a trial to test its effectiveness in patients.”
Professor Harrington, who is also an Honorary Consultant at The Royal Marsden NHS Foundation Trust, said: “Around half of skin cancers carry the BRAF mutation, and while therapies to target this gene are being developed, therapeutic responses are often short lived. Now we have found a way of targeting this type of melanoma more effectively than previous treatments. In the future, targeted melanoma treatments using JNK inhibitors with virus therapy could be used in instances where the disease has spread and radiotherapy is no longer an option.”