Many new anti-cancer drugs inhibit proteins that are essential for the proliferation of cancer cells.
One example is ibrutinib, an innovative therapy for chronic lymphocytic leukaemia first approved in 2014.
Chronic lymphocytic leukaemia is caused by uncontrolled growth of cells from the body’s immune system.
It is the most common leukaemia in the Western world.
Ibrutinib breaks the circle of rampant cell proliferation and allows even patients with high-risk chronic lymphocytic leukaemia to survive for many years.
However, patients must keep taking the drug every day and endure side effects, often severe, including fever, pain, and fatigue.
To improve the treatment of chronic lymphocytic leukaemia toward higher efficacy and fewer side effects, scientists are increasingly exploring combination therapies.
Ideally, such drug combinations exploit vulnerabilities that ibrutinib induces in leukaemia cells, with the ultimate goal of hitting the leukaemia in a hard enough way to later make treatment unnecessary.
To speed up the search for promising drug combinations, a team of scientists at CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences and the Medical University of Vienna developed a method that can effectively sift through a large number of possibilities and identify those drug combinations that have true potential.
The work describing the outcome was published in Nature Chemical Biology.
The new approach combines epigenetic analysis using a method called ATAC-seq (pronounced “attack-sec”) with comprehensive testing of single-cell drug sensitivity.
This approach identified characteristic epigenetic changes in leukaemia cells for patients undergoing ibrutinib treatment.
On top, scientists performed high-throughput imaging, by automated confocal microscopy, to identify drug sensitivities that were specific for these leukaemia cells and not for healthy cells of the very same patient.
All of these experiments were done on primary samples collected from patients before and during ibrutinib treatment, which enabled a systematic analysis of ibrutinib-induced drug vulnerabilities.
Christoph Bock, Principal Investigator at CeMM and corresponding author of the paper emphasises the relevance for personalised medicine: “To keep a cancer at bay, it often takes several drugs at the same time. The search for such combination therapies unfortunately involves a lot of trial and error. This is why we have developed a method that predicts and prioritises what is likely going to work. The first results in chronic lymphocytic leukaemia are promising, and I am convinced that our method will help develop personalised therapies for leukaemia and other cancers.”
Ulrich Jaeger, Professor of Hematology at the Medical University of Vienna and Head of the Clinical Department for Hematology and Haemostaseology at the Vienna General Hospital highlights the medical context of the new method: “Treatment of leukemias with single drugs carries the risk of resistance and failure to respond. A new method to develop combination therapies more systematically indeed constitutes an important advance for cancer research.”
Giulio Superti-Furga, Scientific Director at CeMM and Professor for Medical Systems Biology at the Medical University of Vienna concludes: “The study is a beautiful example for translational medicine and the impact of basic research on clinical praxis. In summary, it provides a powerful method for the rational development of combination therapies and a step toward truly personalised oncology.”