Researchers from the University of Southampton, who were funded by the blood cancer charity Bloodwise, believe that the combination could overcome the problem of resistance to currently available drugs. The research was carried out in collaboration with researchers at the MD Anderson Cancer Center and Portola Pharmaceuticals in the USA.
Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia, with over 4,000 cases in the UK every year. At the moment CLL is incurable, but in recent years, B-cell receptor (BCR) inhibitors have revolutionised treatment. However, some patients can become resistant to these types of drugs, and new therapies are much needed.
One of the reasons for drug resistance is that cancer cells are able to retreat from the blood into the bone marrow, spleen or lymph nodes, where they are protected by surrounding cells that send 'stay alive' signals. By using drugs that attack multiple cancer pathways at once, or combining drugs that have different mechanisms of action, researchers hope to overcome the problems of resistance.
The scientists treated blood cells from CLL patients in the laboratory with a new drug called cerdulatinib, which blocks SYK and Jak, two key cell signalling pathways that promote cancer cell growth. Cells were treated with cerdulatinib alone, or combined with an existing leukaemia drug called venetoclax, which targets leukaemia cells with a specific genetic alteration.
At drug concentrations that would be achievable in patients, cerdulatinib not only blocked the signals that tell cancer cells to grow, but also reversed the protective effect of the surrounding tissues, causing the cells to self-destruct. When researchers combined cerdulatinib with venetoclax, even more cancers cells were killed than by either drug alone.
The findings are published in the journal Clinical Cancer Research.
Dr Andrew Steele, who led the study at the University of Southampton, said: "At the moment, CLL is incurable, and we are now seeing resistance to current treatments. Although this is early work, our results show that cerdulatinib - either alone or in combination with venetoclax - could be a highly effective treatment for this form of leukaemia."
Dr Alasdair Rankin, Research Director at Bloodwise, said: "Drugs like BCR inhibitors have led to huge advances in life expectancy and improvements to the quality of life for patients with CLL. But not all patients respond to these drugs, and we desperately need new treatments. These findings give us hope that combining two drugs with differing mechanisms of actions could combat treatment resistance. The next step will be to show whether these promising results can be replicated in leukaemia patients in clinical trials."
Article: The dual Syk/JAK inhibitor cerdulatinib antagonises B-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia, Matthew D Blunt, Stefan Koehrer, Rachel Dobson, Marta Larrayoz, Sarah Wilmore, Alice Hayman, Jack Parnell, Lindsay D Smith, Andrew Davies, Peter WM Johnson, Pamela B Conley, Anjali Pandey, Jonathan C Strefford, Freda K Stevenson, Graham Packham, Francesco Forconi, Greg P Coffey, Jan Burger and Andrew J Steele, Clinical Cancer Research, doi: 10.1158/1078-0432.CCR-16-1662, published 3 October 2016.