Reference Detail

Ref Type

Journal Article

PMID

(28292940)

Authors

Floc'h N, Ashton S, Taylor P, Trueman D, Harris E, Odedra R, Maratea K, Derbyshire N, Caddy J, Jacobs VN, Hattersley M, Wen S, Curtis NJ, Pilling JE, Pease EJ, Barry ST

Title

Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	16	6	2017 Jun	1031-1040	Mol Cancer Ther

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AZD2811	AZD2811	0	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD2811		AZD-2811\|Barasertib-HQPA\|Defosbarasertib	Aurkb Inhibitors 21	AZD2811 is nanoparticle formulation of Barasertib (AZD1152), which inhibits Aurora kinase B to induce cell cycle arrest and results in tumor regression (PMID: 26865565, PMID: 28292940).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References