Treatment-resistance in patients with one of the most aggressive types of blood cancer may be overcome by combining a new targeted drug called venetoclax with chemotherapy, researchers at the University of Glasgow have shown.

Testing for activity of a cancer gene called 'Trib2' in patients with acute myeloid leukaemia (AML) could identify those people who would most benefit from this targeted treatment. 

Although this is early work, the new treatment combination has the potential to help up to 600 people diagnosed with AML each year in the UK.

The research, which is published in the journal Oncotarget, was funded by the blood cancer research charity Bloodwise with additional funding by Children with Cancer UK, The Howat Foundation, The Children’s Leukaemia Research Project and Friends of Paul O’Gorman.

AML is a highly aggressive form of blood cancer in which immature white blood cells rapidly grow out of control, restricting the production of healthy blood cells. Over 2,400 people are diagnosed with AML each year in the UK. Intensive chemotherapy, followed by a stem cell transplant, currently offers the best chance of a long term cure. But some people are unable to tolerate this treatment, or do not respond, and many more will relapse. 

Researchers found that increased activity of a gene called Trib2 is responsible for the development of particularly chemotherapy-resistant leukaemia cells in around a quarter of AML patients. Trib2 switches on the production of BCL2 proteins, which promote cell survival and regulate against cell death. The BCL2 protein has been linked to treatment resistance in other types of cancer, including lymphoma, breast cancer and prostate cancer.

Leukaemia cells with an active Trib2 gene in mice did not die when subjected to standard chemotherapy. When the researchers added a new targeted drug called venetoclax, which inhibits BCL2 protein production, the Trib2-positive leukaemia cells were sensitised to chemotherapy and treatment resistance was overcome.

The Trib2 gene affects different cells in different ways and in some cells it is known to actually protect against cancer development. By switching the Trib2 gene on and off in different types of healthy blood cells grown in the lab and in mice, the researchers were able to identify the most likely original blood stem cells from which chemotherapy-resistant Trib2-driven AML develops.

It was only in a type of blood stem cell called a ‘granulocyte macrophage progenitor’ cell that Trib2 activity led to the development of fast-growing, treatment-resistant leukaemia cells in mice. Knowing that it is only these cells that lead to chemoresistance will make it easier for tests to identify chemoresistant cells in patients. 

Dr Karen Keeshan, who led the project, said: “Combining BCL2 inhibitors such as venetoclax with standard chemotherapy appears to be extremely effective at overcoming treatment resistance in this aggressive leukaemia in the laboratory.  

“An international clinical trial is currently underway using venetoclax in combination with low dose chemotherapy to treat older patients with AML who cannot tolerate intensive curative chemotherapy. Our findings suggest that testing for Trib2 at diagnosis and relapse could be put in place to identify patients who are most likely to benefit from this targeted treatment.” 

High levels of BCL2 are also linked to chemotherapy resistance in childhood AML, which accounts for 20% of childhood leukaemia. The Glasgow team will investigate whether their findings could be relevant to improving treatment for children with AML as well.

Dr Alasdair Rankin, Director of Research at Bloodwise, said: “The outlook for people with AML is currently extremely poor and new treatments are desperately needed. Fewer than one in five patients will survive for longer than five years after diagnosis and many are not strong enough to undergo curative treatment.

“The more knowledge we have of what has gone wrong in leukaemia cells, the more we will be able to understand and improve treatment strategies and designs. Venetoclax is already licensed for use in chronic lymphocytic leukaemia, for a group of patients with a specific genetic mutation that indicated they will respond to treatment. These findings suggest that this class of drug could be used in a similar way for a significant number of patients with AML too.”

 

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Enquiries: ali.howard@glasgow.ac.uk or elizabeth.mcmeekin@glasgow.ac.uk / 0141 330 6557 or 0141 330 4831

First published: 23 March 2018