Inhibition of the Aurora A kinase augments the anti-tumor efficacy of oncolytic measles virotherapy.

Abstract

Oncolytic measles virus (MV) strains have demonstrated broad spectrum preclinical anti-tumor, including breast cancer. Aurora A kinase controls mitotic spindle formation and plays a critical role in malignant transformation. We hypothesized that, by causing mitotic arrest, the Aurora A kinase inhibitor MLN8237 (alisertib) can increase MV oncolytic effect and efficacy. Alisertib enhanced MV oncolysis in vitro and significantly improved outcome in vivo against breast cancer xenografts. In a disseminated MDA-231-lu-P4 lung metastatic model, the MV/alisertib combination treatment markedly increased median survival to 82.5 days with 20% of the animals being long term survivors vs. 48 days median survival for the control animals. Similarly, in a pleural effusion model of advanced breast cancer, the MV/alisertib combination significantly improved outcome with a 74.5 day median survival versus the single agent groups (57 and 40 days respectively). Increased viral gene expression and IL-24 upregulation were demonstrated, representing possible mechanisms for the observed increase in antitumor effect. Inhibiting Aurora A kinase with alisertib represents a novel approach to enhance measles virus-mediated oncolysis and antitumor effect. Both oncolytic MV strains and alisertib are currently tested in clinical trials, this study therefore provides the basis for translational applications of this combinatorial strategy in the treatment of patients with advanced breast cancer.