Abstract 5486: Developing homing aptamers for targeted therapy in neuroblastoma

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Neuroblastoma is the most common extracranial solid tumour in children. It accounts for 7-10% of malignancies in patients younger than 15 years and 15% of childhood oncology deaths. Each year, there are about 650 new cases of neuroblastoma occurring in the US. The survival rate is 70 - 95 % for low stage (stage 1, 2, 3) tumors. Unfortunately more than 50% of the patients present with advanced stage and the overall survival rate is less than 40% (less than 30% of the children over 1 year old) despite current aggressive multimodal therapies. We have reached the maximal tolerated dosage for most of the chemotherapeutic agents currently used to treat neuroblastoma. Therefore, better targeted therapeutic agents are required to reduce the toxicity related to the therapies. To identify specific targeting agents for neuroblastoma cells, we have undertaken nucleic acid based approach, known as aptamers. Aptamers are short single stranded nucleic acid ligands which can bind specifically to target protein or small molecules because of their unique 3D structures. Low or no immunogenicity together with high specificity makes aptamers potential candidates for therapeutic agents. In our study we have applied Systematic Evolution of Ligands by EXponential Enrichment (SELEX) to isolate RNA aptamers that target neuroblastoma. A modified RNA pool containing a theoretical 109 unique molecules was generated from a synthetic combinatorial library of nucleic acids, by using 2′-F pyrimidine and 2′-OH purine nucleotides in order to increase the stability toward nucleases. We performed 13 rounds of selection against one of the aggressive stage 4 neuroblastoma cell lines, SK-NA-S. After preliminary analysis we have identified 15 modified RNA sequences and performed binding affinity studies by labeling those sequences with 33P. The apparent dissociation constant (Kd) values are in nanomolar range. The aptamers with the lowest Kd values are chosen for further study in order to visualize the site of binding as well as to identify the target protein they are binding to. Once a neuroblastoma specific aptamer is verified, it will be evaluated for targeted therapeutics in neroblastoma by conjugating it with the polymerized liposomal nanoparticles containing small molecule drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5486.