Modeling Dose and Schedule Effects of AZD2811 Nanoparticles Targeting Aurora B Kinase for Treatment of Diffuse Large B-cell Lymphoma

Abstract

Barasertib (AZD1152), a pro-drug of the highly potent and selective Aurora B kinase inhibitor AZD2811, showed promising clinical activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients administered as a 4-day infusion. To improve potential therapeutic benefit of Aurora B kinase inhibition, a nanoparticle formulation of AZD2811 has been developed to address limitations of repeated intravenous infusion. One of the challenges with the use of nanoparticles for chronic treatment of tumors is optimizing dose and schedule required to enable repeat administration to sustain tumor growth inhibition. AZD2811 gives potent cell growth inhibition across a range of DLBCL cells lines in vitro. In vivo, repeat administration of the AZD2811 nanoparticle gave antitumor activity at half the dose intensity of AZD1152. Compared with AZD1152, a single dose of AZD2811 nanoparticle gave less reduction in pHH3, but increased apoptosis and reduction of cells in G1 and G 2 -M, albeit at later time points, suggesting that duration and depth of target inhibition influence the nature of the tumor cell response to drug. Further exploration of the influence of dose and schedule on efficacy revealed that AZD2811 nanoparticle can be used flexibly with repeat administration of 25 mg/kg administered up to 7 days apart being sufficient to maintain equivalent tumor control. Timing of repeat administration could be varied with 50 mg/kg every 2 weeks controlling tumor control as effectively as 25 mg/kg every week. AZD2811 nanoparticle can be administered with very different doses and schedules to inhibit DLBCL tumor growth, although maximal tumor growth inhibition was achieved with the highest dose intensities.

Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

“…The function of Aurora C kinase is not well established, but studies suggested it has similar function to Aurora B kinase ( Sasai et al, 2004 ; Yan et al, 2005 ). There are several Aurora kinase inhibitors that have progressed to clinical development, including tozasertib ( Zhang et al, 2020 ), barasertib ( Floc’h et al, 2019 ) and MK-5108 ( Amin et al, 2016 ). Previous studies showed that GSK-1070916 has a broad antitumor effect on cancer cell lines and in tumor xenograft models including lung, breast, colorectal, and leukemia ( Hardwicke et al, 2009 ).…”

Histone Modifications and Their Targeting in Lymphoid Malignancies

“…Moreover, during the Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 17 November 2021 G2 phase, phospho-H3 co-localizes with the Aurora B kinase which is known to be frequently overrepresented in NHL patients [216,217]. Interestingly, both preclinical [218] and clinical [219] data have supported the potential for the Aurora kinase inhibition as a new therapy for DLBCL patients.…”

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

“…In this context, encapsulation of this type of PROTACs could undoubtedly improve efficacy and reduce toxicity. Novel formulations of this type of chemical entities have shown potential, and some of them like small molecules aurore kinase inhibitors are currently in clinical development (Floc'h et al, 2019). Another limitation of PROTACs is the ubiquitous expression of some of the POI in non-transformed tissues.…”