Selective therapeutic targeting of the anaplastic lymphoma kinase with liposomal siRNA induces apoptosis and inhibits angiogenesis in neuroblastoma

Daniela Di Paolo, Chiara Ambrogio, Fabio Pastorino, Chiara Brignole, Cinzia Martinengo, Roberta Carosio, Monica Loi, Gabriella Pagnan, Laura Emionite, Michele Cilli, Domenico Ribatti, Theresa M. Allen, Roberto Chiarle, Mirco Ponzoni, Patrizia Perri

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2201-2212
Number of pages12
JournalMolecular Therapy
Volume19
Issue number12
DOIs
Publication statusPublished - Dec 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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