Abstract A282: Antitumor activity of alisertib (MLN8237), an investigational small molecule Aurora A kinase inhibitor, as a single agent and in combination with paclitaxel, in experimental models of small cell lung cancer.
Authors: Blair Derek , Zhang Mengkun , Smith Michael D. , Szynal Carmin , Ecsedy Jeffrey A. , Niu Huifeng 
Published: August 2014

Abstract
Alisertib (MLN8237) is a highly selective, potent small molecule inhibitor of Aurora A kinase that is being developed for the treatment of patients with advanced malignancies, including small cell lung cancer (SCLC). SCLC accounts for approximately 13-15% of all lung cancers diagnosed and represents a major unmet medical need. SCLC is an aggressive disease with a median survival of 2-4 months if left untreated. Despite SCLC often being chemosensitive initially, with response rates between 60 - 80%, relapse is almost universal. Here, we assessed the antitumor effects of alisertib in vitro in various SCLC cell lines and in vivo in primary human SCLC xenograft models. The growth inhibitory effect of alisertib was determined in a number of SCLC cell lines. The effect on growth of these lines was measured by two independent methods, after treating these cells for 96 hours with varying concentrations of alisertib. The viability assays used were CyQuant direct, which measures cell proliferation by quantifying DNA content, and PrestoBlue, which determines cell viability by measuring the ability of cells to reduce resazurin. Cell growth was inhibited by alisertib in all lines tested with concentrations producing a 50% inhibition (IC50) ranging from 9 to 34 nM and 8 to 26 nM in the CyQuant and PrestoBlue assays, respectively. The antitumor activity of alisertib as a single agent was also evaluated in a number of primary human SCLC xenografts. In all tumor models tested, alisertib resulted in significant tumor growth inhibition at 20 mg/kg, administered both QD and BID. Alisertib dosed at 20 mg/kg BID in the CTG-0198 model led to regressions in tumor size during the period of dosing. The antitumor activity of alisertib was also tested in combination with a number of standard of care agents including paclitaxel. The combination of alisertib and paclitaxel provided enhanced antitumor activity in comparison to either agent alone in a number of models. These results demonstrate that alisertib effectively inhibits growth of experimental human SCLC models in cell culture, and displays effective antitumor activity in multiple primary human SCLC xenografts, both alone and in combination with paclitaxel. This work provides preclinical support for the further clinical evaluation of alisertib in SCLC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A282.
Citation Format: Derek Blair, Mengkun Zhang, Michael D. Smith, Carmin Szynal, Jeffrey A. Ecsedy, Huifeng Niu. Antitumor activity of alisertib (MLN8237), an investigational small molecule Aurora A kinase inhibitor, as a single agent and in combination with paclitaxel, in experimental models of small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A282.