Abstract 2748: Aurora A kinase inhibitor MLN8237 suppresses neurosphere proliferation of pediatric glioblastoma and prolongs animal survival in patient tumor-derived orthotopic xenograft mouse model

Abstract

Abstract Background: Pediatric glioblastoma (GBM) is highly aggressive and development of novel therapy is needed. Aurora A kinase is critical for mitosis and its overexpression results in malignant transformation of normal cells. MLN8237 (Alisertib) is the first orally available reversible selective inhibitor of the Aurora A serine/threonine kinase. We investigated the effects of MLN8237 on glioma stem cell proliferation and animal survival, as well as the effects on clinically-proven therapy resistant GBM cells. Methods: Levels of Aurora A kinase expression were screened in a panel of patient tumor-derived orthotopic xenograft mouse models. Anti-tumor effects was examined by Cell Counting Kit-8 assay in paired monolayer cell lines (in FBS-based media) and neurosphere cultures (in serum-free media containing EGF and bFGF) from two xenograft mouse models, IC-4687GBM (previously untreated) and IC-R0315GBM (established from a therapy-resistant autopsy sample). Therapeutic efficacy was examined in vivo by orally administered MLN8237 (30 mg/kg/day for 12 days) in NOD/SCID mice (n=10 per group) two weeks post intra-cerebral tumor cell implantation. Tumor growth was examined by MRI and histopathological analysis. Results: Overexpression of Aurora A kinase mRNA (4-10 fold over normal control) was observed in our pediatric GBM models. Tumor growth in FBS medium was suppressed in the previously untreated line (4687GBM) but not in the therapy-resistant line (R0315GBM). Cell growth of neurospheres, which are enriched with cancer stem cells, was suppressed in both GBM lines in a time- and dose-dependent manner. In IC-4687GBM, suppression of xenograft tumor growth was confirmed by MRI and histopathological analysis along with significant prolongation of animal survival in the treatment group. In the therapy-resistant model IC-R0315GBM, no significant suppression was observed, which correlates with the in vitro lack of effect on the monolayer cells. Conclusion: We detected high levels Aurora A kinase expression in pediatric GBM models and demonstrated the efficacy of MLN8237 in targeting GBM in vitro and in vivo. Our data in the therapy-resistant model IC-R0315GBM suggests the need for combination treatment in therapy-resistant GBMs. Our results support the evaluation of MLN8237 as a novel agent for pediatric GBMs. Citation Format: Mari Kogiso, Linna Zhang, Lin Qi, Holly B. Lindsay, Frank Y. Lin, Stacey Berg, Xiao-Nan Li, Jodi A. Muscal. Aurora A kinase inhibitor MLN8237 suppresses neurosphere proliferation of pediatric glioblastoma and prolongs animal survival in patient tumor-derived orthotopic xenograft mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2748. doi:10.1158/1538-7445.AM2014-2748