Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly AML patients. However clinical utility was limited by the requirement for a 7 day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in pre-clinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25mg/kg and 98.7mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumour growth, exceeding the activity of AZD1152. The improved anti-tumour activity was associated with increased phospho-histone H3 inhibition, polyploidy and tumour cell apoptosis. Moreover, AZD2811 nanoparticles increased anti-tumour activity when combined with Ara-C. By modifying dose of AZD2811 nanoparticle therapeutic benefit in a range of pre-clinical models was further optimised. At high dose anti-tumour activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively these data establish that AZD2811 nanoparticles have activity in pre-clinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell cycle agents in this disease.
- Received September 9, 2016.
- Revision received March 7, 2017.
- Accepted March 8, 2017.
- Copyright ©2017, American Association for Cancer Research.