Survivin as a New Target for Neuroblastoma

Background: Neuroblastoma is the most common solid peripheral nervous system pediatric tumor found in pediatrics. Neuroblastoma (NB) commonly metastasizes through the lymphatic system and bone marrow, and has a particularly poor prognosis in children older than 18 months, with five-year survival rates typically around 40-50%. Our group is investigating for less toxic agents against NB cells. We found that Tolfenamic acid (TA), a small molecule had anti-cancer effects in high risk neuroblastoma (HRNB) cell lines. Survivin has been associated with poor prognosis in several types of cancers. Survivin is a protein that specifically inhibits the caspase apoptotic proteins thus negatively regulating apoptosis. We conducted a search of various databases in order to investigate the association of Survivin with the survival of NB patients. The other objective was to test an agent that could target Survivin an inhibit NB cell growth. Materials: We utilized R2 genomics and visualization platform to generate survival curves, looking specifically at overall and relapse-free survival probabilities in NB patients. The graphs were made using the data from 88 patients. We also used NB cell line for in vitro testing. SH-SY 5Y cells were cultured it in the presence of copper TA and cell viability was assessed at 24 and 48 hours. Protein extracts were prepared and analyzed for the expression of Survivin using Western blot analysis. Results: We found that the overall survival probability for NB patients with high expression of Survivin had a significantly poorer prognosis (p: 8.5e-9), than those with lower expression of Survivin. Similarly, the relapse-free survival probability curve also demonstrated that high expression of Survivin was associated with a poorer prognosis (p: 1.9e-6) than patients who had lower expression levels. Thus demonstrating that there is a strong association with high Survivin expression and poor prognosis. We also found that Cu-TA acted as an effective inhibitor to Survivin in our laboratory research with the SHSY-5Y cell line. Conclusion: The survival curves showed a strong association of Survivin with poor prognosis. The complexed agent, Cu-TA acts as an efficacious inhibitor of the HRNB cell line SHSY-5Y potentially inhibiting Survivin. Going forward, further research should be done to identify novel less toxic therapeutic agents to target Survivin, in hopes of better treating HRNB cell lines.