Researchers found the combination of ibrutinib, a targeted treatment already in clinical use, with a new inhibitor called AZD8055, helped promote CLL cell death in a preclinical study.
The research, carried out in a collaboration between the University of Glasgow and NHS Greater Glasgow and Clyde is published in Clinical Cancer Research,
The study, which used CLL patient samples and a CLL mouse model, found that combination of these two inhibitors activated a protein called FOXO1, which can function as a “molecular brake”, stopping the cells from multiplying and inducing CLL cell death.
CLL is a blood cell cancer affecting white blood cells and more commonly affects people over the age of 60.
The disease varies from patient to patient, with some people experiencing a stable low-grade disease which does not require treatment, while others develop resistance to chemotherapy treatments given and are considered “high-risk” patients.
The introduction of ibrutinib into the clinic as a treatment of high-risk CLL patients has enhanced the survival of this difficult to treat subset of CLL patients.
However, the CLL cells can adapt to the drugs, developing mutations becoming resistant to ibrutinib leaving few therapeutic options for patients.
Novel combination of treatments offer the potential to reduce the ability of the CLL cell to adapt to the treatment which attacks the cell in two places as opposed to one.
Dr Alison Michie, who led the study, said: “Reducing the ability of CLL cells to survive is key to interrupting disease progression. We established that by targeting and inhibiting the function of a protein called mTOR, often deregulated in cancer, we improved the killing of CLL cells.”
Dr Michie added: “Combining mTOR inhibition with a drug called ibrutinib, currently used in the clinic to treat high-risk CLL patients, enhances the activation of FOXO1, a protein that can promote cell death, in a preclinical model. Our findings are important because they could demonstrate a potential new therapeutic approach for treating patients with high-risk CLL.”
The study was funded by the Medical Research Council and Bloodwise.