Doublecortin-like kinase : a potential therapeutic target for neuroblastoma

Abstract

There is an urgent need for a better and more effective therapy for neuroblastoma, a pediatric tumor of the sympathetic nervous system. Despite intensive treatment, less than 50 % of the patients with high-risk neuroblastoma survive. Therefore we have investigated if doublecortin-like kinase is a potential therapeutic target for neuroblastoma. Doublecortin-like kinase (DCLK1) gene encodes doublecortin-like (DCL) and DCLK-long that are crucial for correct proliferation and differentiation of neuroblasts. We found that these proteins are overexpressed in human neuroblastomas and gliomas but not in other tumors or normal tissue. DCL/DCLK-long knockdown in mouse and human neuroblastoma cells resulted in apoptotic cell death. We also found that DCL is involved in the control of mitochondrial activity, energy production and neuroblastoma cell proliferation. In vivo, we observed delayed tumor growth in neuroblastoma tumor xenografts with inducible DCL knockdown. Moreover, we showed that combining DCL/DCLK-long knockdown with low doses of vinca alkaloids results in a synergistic apoptotic effect, confirming that this is a potential approach to consider for neuroblastoma therapy. In conclusion, the data presented in this thesis provide new insights in the biological function of the DCLK1 gene and indicate that DCL and DCLK-long are potential therapeutic targets for neuroblastoma.