The Novel Orally Active Aurora A Kinase Inhibitor MLN8237 Is Highly Active in Preclinical Models of Acute Myeloid Leukemia and Significantly Increases the Efficacy of Cytarabine.

Abstract 2087

Poster Board II-64

Acute myeloid leukemia (AML) most frequently affects the elderly, many of whom are unable to tolerate intensive chemotherapy. Therefore, improvements in clinical outcomes for patients with AML largely depend upon the development of novel targeted therapies. Aurora A is a serine/threonine kinase that plays a key role in mitosis by regulating the G2-M transition, centrosome separation, spindle assembly and chromosome segregation. It is overexpressed in AML and has been implicated in genetic instability, disease progression and drug resistance. MLN8237 is a novel orally available Aurora A inhibitor that has entered Phase I and Phase II trials for cancer therapy. Based on the critical role of Aurora A in cell cycle regulation and its intrinsic overexpression in AML cells, we hypothesized that MLN8237 would possess significant antileukemic activity. We tested our hypothesis in established human AML cell lines, primary AML patient specimens, and a mouse model of AML. MLN8237 potently inhibited the in vitro growth and survival of all AML cell lines and primary human AML cells from patients with newly diagnosed AML and patients with relapsed, chemotherapy resistant disease. Mechanistic studies showed that MLN8237 reduced the activity of Aurora A kinase as evidenced by reduced phosphorylation of Aurora A at Thr288. MLN8237 treatment also disrupted normal cell cycle kinetics and induced apoptosis in a dose- and time-dependant manner characterized by the accumulation of G2/M and aneuploid cells prior to the onset of apoptosis. Exposure to MLN8237 led to activation of FOXO3a followed by a dose-dependent increase in the expression of its transcriptional target Bim. These events appear to be important mediators of the pro-apoptotic effects of this agent. We next investigated the ability of MLN8237 to increase the efficacy of cytarabine in AML. Treatment with the combination of MLN8237 and cytarabine resulted in significantly greater apoptosis and more effective inhibition of survival than treatment with either agent alone in AML cell lines and primary patient specimens. MLN8237 and cytarabine cooperated to enhance mitochondrial-mediated apoptosis as evidenced by increased processing of caspases-9 and -3 to active forms. Daily oral administration of MLN8237 to immunodeficient mice bearing AML xenografts was well tolerated, effectively reduced tumor growth and led to the disruption of mitotic spindles and centrosome amplification. Moreover, MLN8237 significantly enhanced the activity of cytarabine to achieve tumor regression. Our data demonstrates that MLN8237 has a multifaceted mechanism of action comprised of pro-apoptotic and growth inhibitory effects. Our collective findings indicate that the combination of MLN8237 and cytarabine represents a novel, very promising therapeutic strategy for AML. A clinical study investigating the safety and efficacy of this combination in patients with refractory AML is planned.