Poster Presentation Advances in Neuroblastoma Research Congress 2016

Aurora Kinase A inhibition sensitizes neuroblastoma to 131I -MIBG (#173)

W. Clay Gustafson 1 , Katherine K Matthay 1 , Aleksandra Olow 1 , Melanie Regan 1 , Erin Nekritz 1 , Carolyn Tu 1 , DuBois Steven 2 , Haas-Kogan Daphne 3 , William Weiss 1 , Youngho Seo 1
  1. University of California San Francisco, San Francisco, CA, United States
  2. Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  3. Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Background: Despite the use of intensive multimodal therapy, a substantial proportion of children with high-risk neuroblastoma have relapsed or refractory disease.. Novel agents and approaches are needed to improve outcomes. Targeted radiotherapy with 131I -MIBG is one of the most effective salvage therapies for relapsed or refractory neuroblastoma, but the majority of patients do not respond to 131I-MIBG. Aurora Kinase A (AURKA) inhibition has the potential to sensitize tumors to radiation by recruiting cells into G2/M phase. The AURKA inhibitor alisertib has shown efficacy in preclinical models for neuroblastoma and is currently in early phase testing in patients with neuroblastoma.

Methods: We tested alistertib alone and in combination with radiation therapy on cultured neuroblastoma cell lines and with 131I –MIBG in vivo in a subcutaneous xenograft for efficacy and effects on cell cycle as well as the p53 apoptotic pathway.

Results: Alisertib caused G2/M phase arrest in neuroblastoma cells and significantly improved efficacy when combined with both external beam radiation in cultured cells. Alisertib combined with 131I –MIBG yielded superior growth inhibition compared to either agent alone when tested in a mouse model of norepinephrine transporter (hNET) positive, radiation-resistant neuroblastoma.

Conclusions: The combination of alisertib and 131I -MIBG shows at least additive activity in preclinical testing and provides preclinical rationale for combination testing in clinical trials.