American Association for Cancer Research
15357163mct160580-sup-170635_2_supp_3890658_lm8gkk.doc (3.87 MB)

Supplementary Figures S1-S4 and Tables S1-S2 from Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles

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journal contribution
posted on 2023-04-03, 14:41 authored by Nicolas Floc'h, Susan Ashton, Paula Taylor, Dawn Trueman, Emily Harris, Rajesh Odedra, Kim Maratea, Nicola Derbyshire, Jacqueline Caddy, Vivien N. Jacobs, Maureen Hattersley, Shenghua Wen, Nicola J. Curtis, James E. Pilling, Elizabeth J. Pease, Simon T. Barry

Supplementary figues and tables: Figure S1. In vitro AZD1152-hQPA reduces proliferation and induces polyploidy across a panel of human AML cancer cell lines. Figure S2. AZD1152 has a modest effect on the growth of the HL-60 xenograft models in SCID mice Figure S3. AZD1152 in combination with Ara-C has a modest effect on the growth of the HL-60 xenograft models in SCID mice Figure S4. AZD2811 affect the neutrophil count in a dose-dependent manner Table S1: Cytogenetics of the different cell lines Table S2: Summary table of the pIC50 and nuclear area.



Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (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 preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor 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 preclinical 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. Mol Cancer Ther; 16(6); 1031–40. ©2017 AACR.

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