Combination therapy with an Aurora B kinase inhibitor AZD1152 and AraC, shows enhanced tumouricidal activity in a preclinical model of acute myeloid leukaemia (AML)


Session type:

Rajesh Odedra1, Robert W. Wilkinson1, Sarah V. Holt2, John R. Foster1, Elizabeth Anderson1
1AstraZeneca, Alderley Park, United Kingdom,2Paterson Institute of Cancer Research, Manchester, United Kingdom


Acute myeloid leukaemia (AML) is characterized by an overproduction of abnormal hematopoietic cells in the bone marrow and peripheral blood. Resistance to therapy is a major obstacle in the treatment of AML and underlies the need to develop new treatments. The Aurora kinases play a critical role in mitosis and have been suggested as targets for cancer therapy due to their overexpression in a variety of tumours.  AZD1152 is a selective Aurora B kinase inhibitor that shows anti-tumour activity in a range of preclinical cancer models1, 2. Cytarabine (Ara-C) is used as a clinical therapy for AML.


In this study, we treated SCID mice bearing subcutaneous human AML tumour (HL60) xenografts with AZD1152 (25mg/kg once daily i.p. for 4 days) or AraC (25mg/kg twice daily i.p. for 2 days) as monotherapies or together  in two overlapping combination schedules [either AZD1152 (Day 1-4) plus AraC (Day 1-2) (SCHEDULE 1) or AZD1152 (Day 1-4) plus AraC (Day 3-4) (SCHEDULE 2)].


As monotherapy, both drugs produced significant tumour growth inhibition (TGI) compared to control animals (Maximum TGI of 31.7% & 48.3% for AraC & AZD1152 respectively, both p<0.05). When dosed in combination, both dosing schedules produced enhanced anti-tumour activity compared to controls (Maximum TGI of 110.9% for SCHEDULE 1 & 76.2% for SCHEDULE 2, both p<0.05). Additionally, the data suggest that the combination SCHEDULE 1 was more effective in inhibiting tumour growth compared to combination SCHEDULE 2. Histological analysis of tumours showed a decrease in mitotic cells and an increase in apoptotic cells in drug treated tumours compared to control tumours.  There was an increased level of apoptosis in SCHEDULE 1 treated group compared to SCHEDULE 2 treated group.


These data indicate a potential strategy of combining AZD1152 and AraC for treatment of AML, and suggest that schedule of drug administration may have a consequence on the overall anti-tumour efficacy.