Abstract 5423: Novel targeted therapy for neuroblastoma: Silencing the MXD3 gene using siRNA

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Neuroblastoma is a cancer of the sympathetic nervous system and the most common extracranial solid tumor in children. Almost half of neuroblastoma patients have a high-risk phenotype at diagnosis: metastatic disease. Prognosis of these patients is very poor with only 30% survival despite the most intensive therapies currently available. In addition, patients who respond successfully to treatment suffer from side effects from chemo and radiation therapies, leading to life-long irreversible complications. Therefore, there is a desperate need for a neuroblastoma-targeted therapy that is more effective and has fewer side effects than conventional therapies. Our goal is to develop a molecular-targeted therapy that can be used in tandem with current treatments. In our previous study, we identified the transcription factor MXD3 as a novel molecular target for neuroblastoma (presented in the 2013 AACR annual meeting). In the current study, we demonstrated in vitro efficacy of an MXD3 targeted therapeutic using siRNA and nanoparticles. We have developed MXD3 targeting methods using MXD3 siRNA and superparamagnetic iron oxide nanoparticles (NPs). We assembled siRNA on the surface of NPs and introduced them to SK-N-DZ cells (neuroblastoma cell line with high MXD3 expression) in vitro. Upon a single treatment with the siRNA-NP-complexes, the siRNAs were successfully delivered into the cells and MXD3 knockdown was confirmed at the protein level as early as 4 hours post treatment. The cells treated with the MXD3 siRNA-NP-complexes showed significantly decreased proliferation compared to those treated with control siRNA-NP-complexes or untreated cells (p <0.05). We further investigated the mechanism of MXD3 knockdown in neuroblastoma cells. The SK-N-DZ cells treated with the MXD3 siRNA-NP-complexes were more annexin V positive and had increased caspase activities (p <0.05) than those treated with control siRNA-NP-complexes or untreated cells. We further tested whether additive effects were observed between the MXD3 siRNA-NP-complexes and conventional chemotherapy drugs. In vitro treatment effects with the MXD3 siRNA-NP-complexes was enhanced by doxorubicin and vincristine at IC50 doses, both of which are commonly used in the current treatment of neuroblastoma. In conclusion, we have demonstrated novel in vitro delivery of the MXD3 siRNA-NP complexes into neuroblastoma cells. We have also shown that MXD3 knockdown induced apoptosis and inhibited cell proliferation. Furthermore, we showed additive effects of the MXD3 siRNA-NP complexes with doxorubicin and vincristine. Further work is ongoing to determine the therapeutic effects in other neuroblastoma cell lines with different MXD3 expression and side effects in normal blood cells. The future plan is to optimize our nanocomplexes for efficient in vivo delivery, which is the major hurdle in the development of siRNA-based therapeutics. Citation Format: Connie Duong, Cathy Chen, Sakiko Yoshida, Gustavo Barisone, Jan Nolta, Elva Diaz, Nitin Nitin, Noriko Satake. Novel targeted therapy for neuroblastoma: Silencing the MXD3 gene using siRNA. [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 5423. doi:10.1158/1538-7445.AM2014-5423