title: Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles.
abstract: 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.
authors.affiliation: IMED Oncology, AstraZeneca, Cambridge, United Kingdom.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floc'h
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Susan
authors.initials: S
authors.lastname: Ashton
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Paula
authors.initials: P
authors.lastname: Taylor
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Dawn
authors.initials: D
authors.lastname: Trueman
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Harris
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.affiliation: IMED Drug Safety & Metabolism, AstraZeneca, Gatehouse Park, Waltham, Boston, Massachusetts.
authors.forename: Kim
authors.initials: K
authors.lastname: Maratea
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Derbyshire
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Caddy
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Vivien N
authors.initials: VN
authors.lastname: Jacobs
authors.affiliation: IMED Oncology, AstraZeneca, Gatehouse Park, Waltham, Boston, Massachusetts.
authors.forename: Maureen
authors.initials: M
authors.lastname: Hattersley
authors.affiliation: IMED Oncology, AstraZeneca, Gatehouse Park, Waltham, Boston, Massachusetts.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Wen
authors.affiliation: IMED Oncology, AstraZeneca, Macclesfield, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtis
authors.affiliation: IMED Discovery Sciences, AstraZeneca, Cambridge, United Kingdom.
authors.forename: James E
authors.initials: JE
authors.lastname: Pilling
authors.affiliation: IMED Discovery Sciences, AstraZeneca, Cambridge, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Pease
authors.affiliation: IMED Oncology, AstraZeneca, Cambridge, United Kingdom. simon.t.barry@astrazeneca.com.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Barry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D053758:Nanoparticles; D010755:Organophosphates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D003561:Cytarabine; D064107:Aurora Kinase B