Elizabeth Janet Pease

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

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.

Abstract 311: Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers

A nanoparticle formulation of AZD2811, a selective aurora kinase B inhibitor, is currently under clinical development for the treatment of both haematological and solid tumour disease. AZD2811 is the active derivative of the prodrug Barasertib (AZD1152) which gave promising clinical activity in elderly AML patients delivered as a 7-day infusion (Kantarjian et al, Cancer, 119, 2611-2619, 2013). To address the limitations associated with the clinical utility of Barasertib and other cell cycle inhibitors in the clinic, AZD2811 has been incorporated into an AccurinTM nanoparticle using a pamoic acid ion pairing approach to optimise drug release rate (Song et al, Journal of Controlled Release, 229, 106-119, 2016), improve the drug exposure to tumour and reduce the duration of administration. A proof of principle formulation of AZD2811 as an AccurinTM nanoparticle established the principle that anti-tumour activity and improved therapeutic index could be achieved (Ashton et al, Science Translational Medicine, 325, 1-10, 2016). The clinical nanoparticle formulation of AZD2811 has been optimised for drug loading and release rate. In pre-clinical models, the clinical formulation can be used flexibly to optimise drug delivery for use in both haematological disease such as AML, or in solid tumour settings. Anti-tumour activity in solid tumours can be achieved at doses where bone marrow toxicity is reduced compared to Barasertib. In sensitive xenograft and PDX solid tumour models greater than 90% tumour regression is observed after a total dose of 50mg/kg with no tumour progression for greater than 40 days. In contrast, for AML, increasing the dose intensity by 2-4 fold leads to neutropenia and to complete tumour regression in a range of AML xenograft models for greater than 60 days. These data establish the concept that drug delivery using nanoparticles is able to resolve therapeutic index challenges, and is able to do so across different disease types. AZD2811 is currently in Phase 1 clinical trial (D6130C0000). The current pre-clinical and clinical data with this novel approach to inhibition of the cell cycle will be discussed. Citation Format: Susan Ashton, Nicholas Floch, Paula Taylor, Colin Howes, Doug Ferguson, Matthew Ling, Maureen Hattersley, Shenghua Wen, Kim Maratea, Adina Hughes, Sean Redmond, Wolfram Brugger, Simon Smith, Alexander MacDonald, Keith Parry, Howard Burris, Young-Ho Song, Jim Nolan, Elizabeth Pease, Simon T. Barry. Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 311. doi:10.1158/1538-7445.AM2017-311

Abstract 3769: Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial cell carcinoma

Urothelial Cell Carcinoma (UCC) is the fifth most common cancer, but no new generation molecularly targeted therapies have been registered to treat this disease. Non muscle-invasive bladder cancer can be treated by systemic or intravesical dosing routes. However, the urothelium is one of the most formidable permeability barriers in nature, and may limit the penetration of small molecules into tumour tissue from the intravesical location. Inhibitors of mitosis, including spindle proteins such as Eg5, are attractive targets for cancer therapy, but their efficacy when dosed systemically is severely limited by bone marrow toxicities such as neutropenia and thrombocytopenia. AZ9814, a very potent and selective small molecule inhibitor of Eg5, induces apoptosis and inhibits proliferation of UCC cells in culture with a GI50 of Citation Format: Leigh Williams, Rebecca Ellston, Dawn Trueman, Helen Musgrove, Linette Ruston, Brian Aquila, Elizabeth Pease, Stephanie Klein, Barry R. Davies. Continuous, low intensity systemic dosing maximizes the therapeutic margin of Eg5/KSP inhibition in an orthotopic model of urothelial cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3769.