The anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is 
involved in the pathogenesis of different types of human cancers, including 
neuroblastoma (NB). In NB, ALK overexpression, or point mutations, are 
associated with poor prognosis and advanced stage disease. Inhibition of ALK 
kinase activity by small-molecule inhibitors in lung cancers carrying ALK 
translocations has shown therapeutic potential. However, secondary mutations may 
occur that, generate tumor resistance to ALK inhibitors. To overcome resistance 
to ALK inhibitors in NB, we adopted an alternative RNA interference (RNAi)-based 
therapeutic strategy that is able to knockdown ALK, regardless of its genetic 
status [mutated, amplified, wild-type (WT)]. NB cell lines, transduced by 
lentiviral short hairpin RNA (shRNA), showed reduced proliferation and increased 
apoptosis when ALK was knocked down. In mice, a nanodelivery system for 
ALK-specific small interfering RNA (siRNA), based on the conjugation of 
antibodies directed against the NB-selective marker GD(2) to liposomes, showed 
strong ALK knockdown in vivo in NB cells, which resulted in cell growth arrest, 
apoptosis, and prolonged survival. ALK knockdown was associated with marked 
reductions in vascular endothelial growth factor (VEGF) secretion, blood vessel 
density, and matrix metalloproteinases (MMPs) expression in vivo, suggesting a 
role for ALK in NB-induced neoangiogenesis and tumor invasion, confirming this 
gene as a fundamental oncogene in NB.