New research shows that a combination of two existing drug types slows the growth of kidney cancer by suppressing the development of new tumour blood vessels more effectively than existing treatments.
In laboratory-based studies, scientists at The Institute of Cancer Research, London, showed that a combination of drugs – a tyrosine kinase inhibitor and a MEK inhibitor – could work together in kidney cancer. The work is published in the journal Molecular Cancer Therapeutics.
Kidney cancer is driven by aggressive blood vessel growth, known as angiogenesis, and angiogenesis inhibitors such as sunitinib – a tyrosine kinase inhibitor – are licensed for the treatment of kidney cancer.
However, these cancers can quickly become resistant to these anti-angiogenic drugs, allowing the disease to progress. The mechanisms that mediate resistance to these anti-angiogenic drugs are poorly understood.
In the study, jointly funded by Breast Cancer Now and the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the ICR, the researchers examined the blood vessels in tumours that were resistant to sunitinib.
They found that an important signalling pathway that allows blood vessels to grow – the Ras-Raf-MEK-ERK1/2 signalling pathway – was hyperactive in tumour vessels of resistant tumours.
This provided a rationale for trying MEK inhibitor drugs – which target that pathway – in combination with tyrosine kinase inhibitors.
The researchers examined several MEK inhibitors for their ability to suppress blood vessel growth. They found that the MEK inhibitor trametinib was very effective.
In experiments in mice, they then showed that the combination of trametinib with sunitinib was more effective in suppressing tumour growth than either drug alone.
After 40 days of treatment with both drugs, average tumour volume was lower than it had been at the start of the study. This was in contrast to sunitinib treatment alone over the same time period, where the tumour volume tripled compared with the start of the study.
The researchers also built in a ‘treatment break’ to some of the studies in mice, showing that the combination of drugs still worked with gaps between doses. This was an important step, because taking both types of drug simultaneously could lead to toxic side-effects – but treatment breaks could allow patients to benefit from the combined effects of the drugs without developing unmanageable side effects.
The researchers also showed that combining trametinib with a different tyrosine kinase inhibitor, called pazopanib, was effective. This is important, because this combination has already been shown to be safe in a phase I human trial. This work could pave the way for a study to test the combination of trametinib with pazopanib in patients with advanced kidney cancer.
Study leader Dr Andrew Reynolds, Leader of the Tumour Biology team at ICR, said: “One of the greatest challenges in cancer treatment is to tackle cancer’s ability to evolve and change, because this allows the cancer to become resistant to existing treatments. One way to tackle this resistance is to use rational combinations of existing drugs.”
“Our results show the clear potential of combining drugs to treat drug-resistant renal cell carcinoma, which claims several thousand lives in the UK each year. Our study provides a strong rationale for clinical trials of the combination in people affected by the disease.”