Rationalizing responses to Aurora B inhibitors in leukaemia

Acute myeloid leukaemia (AML), the most common form of acute leukaemia, remains incurable for most patients. New targeted therapies based on kinase inhibitors are being tested in AML, but not all patients benefit to the same extent, highlighting the need for personalized treatments. Previous work has shown promise for Aurora B inhibitors in AML. Here, the student will take proteomic and system biology approaches to investigate the mechanisms that sensitize AML cells to Aurora B targeted therapy. In addition to advancing our understanding of Aurora B role in cancer biology, this work has the potential to impact AML personalized therapy.

Aurora kinases play prominent roles in cancer biology (Ref 1) and clinical trials evaluating Aurora B inhibitors in acute myeloid leukaemia (AML) are showing promise. However, not all patients respond to these therapies to the same extent and the mechanisms that allow cancer cells to evade treatment are not fully understood. The aim of this project is to investigate the mode of action of Aurora B inhibitors in AML cells and the biochemical mechanisms that make cancer cells sensitive or resistant to these compounds. To this end, the student will compare the wiring of biochemical networks in cell lines of different sensitivity profile to Aurora B inhibitors and will investigate how such biochemical wiring changes upon therapy. This will be achieved by using state-of-the-art proteomic and phosphoproteomic methods in combination with computational approaches to derive biochemical network topology from such datasets. These methodologies are well developed in the host laboratory and their application in different cancer models has shown that responses to kinase inhibitors are determined by the combination of the activity of both the target and parallel pathways (Refs 2-5). The hypotheses generated with the initial cell-based work will be tested in additional AML cell lines, primary AML samples obtained from the BCI tissue biobank and in those derived from current and planned Aurora B inhibitors clinical trials in AML. In addition to advancing our understanding of how Aurora B
controls cancer biology, signatures associated with patient responses may represent biomarkers for patient stratification and personalized medicine.
The project will train the student in mass spectrometry-based proteomics and computational biology applied to the investigation of intracellular cell signaling and cancer research. These unique combination of skills are in short supply in the UK and are highly valued by industry and academia.