Abstract 858: Potent in vivo activity of the aurora kinase inhibitor ABT-348 in human acute myeloid leukemia and myelodysplastic syndrome xenograft models

Abstract

Abstract The Aurora kinases are a family of serine/threonine kinases that mediate essential functions in cell division. Aurora A depletion results in accumulation of cells in the G2/M phase and apoptosis. Inhibition of Aurora B/C results in abnormal cell division, polyploidy, resulting in apoptosis, therefore, Aurora kinases present an attractive target for chemotherapy. Cells treated with aurora inhibitors enter mitosis with normal kinetics but fail to undergo cytokinesis due to mitotic spindle checkpoint disruption. ABT-348 is a novel adenosine triphosphate (ATP)-competitive inhibitor of Aurora A, Aurora B, and Aurora C (Enzyme IC50 A=116, B=5, C= 1 nM) and a potent inhibitor of all members of the VEGF and PDGF family of receptor tyrosine kinases (RTKs). Despite significant advances in the epidemiological, genetic and biological understanding of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), the basic therapeutic approach has not substantially changed for the last 10-15 years, so most patients still die of this disease. Here we demonstrate profound in vivo efficacy (with regressions) of ABT-348 in both AML (MV-4-11, FLT3 mutant expressing the internal tandem duplication with constitutive kinase activation) and MDS (SKM-1) xenograft models. MV-4-11 tumor-bearing SCID mice were treated at 6.25, 12.5 and 25 mg/kg/day, p.o., q7d x 3 (%TGI ratios on day 30 were 80, 86 and 94%, respectively). SKM-1 tumor-bearing SCID mice were treated at 6.25, 12.5 and 25 mg/kg/day, p.o., q7d x 3 (% tumor growth inhibition or TGI ratios on day 30 were 38, 59 and 80%, respectively). In addition, ABT-348 provided additive effects when combined with cytarabine, decitabine or doxorubicin compared to cytotoxic monotherapies. The treatments were well tolerated with no animal health concerns observed indicating the feasibility of ABT-348 combination strategies in the clinic. Currently ABT-348 is being evaluated (monotherapy and in combination with cytotoxic therapies) in the HL-60 acute promyelocytic leukemia xenograft model in vivo. Dose/scheduling studies for combination therapies in the SKM-1 and HL-60 xenografts are ongoing. Pharmacokinetic/pharmacodynamic biomarker analyses in these xenograft models were evaluated using phospho-H3 (an Aurora B substrate, proliferation) and cleaved caspase-3 (apoptosis) by IHC at various timepoints post single dose (1/2 hr to 5 days). A general decrease in proliferation and increase in apoptosis consistent with the mechanism of action was observed which coincided with the potent in vivo efficacy in xenograft models. Overall, ABT-348 is a potent, oral Aurora kinase inhibitor, demonstrating robust in antitumor activity in AML and MDS xenograft models with a good safety profile that warrants investigation in the clinic. ABT-348 is currently undergoing Phase I clinical trials in advanced hematologic malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 858. doi:1538-7445.AM2012-858